Cell surface protein–protein interaction profiling for biological network analysis and novel target discovery

Abstract

The secretome is composed of cell surface membrane proteins and extracellular secreted proteins that are synthesized via secretory machinery, accounting for approximately one-third of human protein-encoding genes and playing central roles in cellular communication with the external environment. Secretome protein–protein interactions (SPPIs) mediate cell proliferation, apoptosis, and differentiation, as well as stimulus- or cell-specific responses that regulate a diverse range of biological processes. Aberrant SPPIs are associated with diseases including cancer, immune disorders, and illness caused by infectious pathogens. Identifying the receptor/ligand for a secretome protein or pathogen can be a challenging task, and many SPPIs remain obscure, with a large number of orphan receptors and ligands, as well as viruses with unknown host receptors, populating the SPPI network. In addition, proteins with known receptors/ligands may also interact with alternative uncharacterized partners and exert context-dependent effects. In the past few decades, multiple varied approaches have been developed to identify SPPIs, and these methods have broad applications in both basic and translational research. Here, we review and discuss the technologies for SPPI profiling and the application of these technologies in identifying novel targets for immunotherapy and anti-infectious agents.

Keywords

secretome protein–protein interaction / receptor–ligand interaction / deorphanization / high-throughput screening

References

[1] Tjalsma H , Bolhuis A , Jongbloed JDH , et al. Signal peptide-dependent protein transport in Bacillus subtilis: a genome-based survey of the secretome. Microbiol Mol Biol Rev 2000; 64: 515- 47.

[2] Ganesan B . Chapter 5 - Aspergillus secretome: an overview. In: Gupta VK (ed.), New and Future Developments in Microbial Biotechnology and Bioengineering. Amsterdam: Elsevier, 2016, 69- 77.

[3] Agrawal GK , Jwa NS , Lebrun MH , et al. Plant secretome: unlocking secrets of the secreted proteins. Proteomics 2010; 10: 799- 827.

[4] Uhlén M , Karlsson MJ , Hober A , et al. The human secretome. Sci Signal 2019; 12: eaaz0274.

[5] Reithmeier RAF . Chapter 16—Assembly of proteins into membranes. In: Vance DE, and Vance JE (eds.), New Comprehensive Biochemistry, Vol. 31. Amsterdam: Elsevier, 1996, 425- 71.

[6] Shikano S , Colley KJ . Secretory pathway. In: Lennarz WJ, and Lane MD (eds.), Encyclopedia of Biological Chemistry (2nd edn). Waltham: Academic Press, 2013, 203- 9.

[7] Rutz C , Klein W , Schülein R . Chapter twelve - N-terminal signal peptides of G protein-coupled receptors: signifcance for receptor biosynthesis, trafficking, and signal transduction. In: Wu G (ed.), Progress in Molecular Biology and Translational Science, Vol. 132. San Diego: Academic Press, 2015, 267- 87.

[8] Gee HY , Kim J , Lee MG . Unconventional secretion of transmembrane proteins. Semin Cell Dev Biol 2018; 83: 59- 66.

[9] Cullen PJ , Steinberg F . To degrade or not to degrade: mechanisms and signifcance of endocytic recycling. Nat Rev Mol Cell Biol 2018; 19: 679- 96.

[10] Bausch-Fluck D , Hofmann A , Bock T , et al. A mass spectrometricderived cell surface protein atlas. PLoS One 2015; 10: e0121314.

[11] Bausch-Fluck D , Goldmann U , Müller S , et al. The in silico human surfaceome. Proc Natl Acad Sci U S A 2018; 115: E10988- 97.

[12] Gu Y , Cao J , Zhang X , et al. Receptome profling identifes KREMEN1 and ASGR1 as alternative functional receptors of SARS-CoV-2. Cell Res 2022; 32: 24- 37.

[13] Pawar S , Kutay U . The diverse cellular functions of inner nuclear membrane proteins. Cold Spring Harb Perspect Biol 2021; 13: a040477.

[14] Mudumbi KC , Czapiewski R , Ruba A , et al. Nucleoplasmic signals promote directed transmembrane protein import simultaneously via multiple channels of nuclear pores. Nat Commun 2020; 11: 2184.

[15] Giacomello M , Pyakurel A , Glytsou C , et al. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol 2020; 21: 204- 24.

[16] Eaglesfeld R , Tokatlidis K . Targeting and insertion of membrane proteins in mitochondria. Front Cell Dev Biol 2021; 9: 803205.

[17] Uhlén M , Fagerberg L , Hallström BM , et al. Proteomics: tissue-based map of the human proteome. Science 2015; 347: 1260419.

[18] Chen W , Liu P , Wang Y , et al. Characterization of a soluble B7-H3 (sB7-H3) spliced from the intron and analysis of sB7-H3 in the sera of patients with hepatocellular carcinoma. PLoS One 2013; 8: e76965.

[19] Kontos F , Michelakos T , Kurokawa T , et al. B7-H3: an attractive target for antibody-based immunotherapy. Clin Cancer Res 2021; 27: 1227- 35.

[20] Lambert DW , Yarski M , Warner FJ , et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 2005; 280: 30113- 9.

[21] Yeung ML , Teng JLL , Jia L , et al. Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the reninangiotensin system. Cell 2021; 184: 2212- 28.e12.

[22] Snider J , Kotlyar M , Saraon P , et al. Fundamentals of protein interaction network mapping. Mol Syst Biol 2015; 11: 848.

[23] Wood L , Wright GJ . Approaches to identify extracellular receptorligand interactions. Curr Opin Struct Biol 2019; 56: 28- 36.

[24] Wishart DS , Knox C , Guo AC , et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 2006; 34: D668- 672.

[25] da Cunha JP , Galante PA , de Souza JE , et al. Bioinformatics construction of the human cell surfaceome. Proc Natl Acad Sci U S A 2009; 106: 16752- 7.

[26] Wojtowicz WM , Vielmetter J , Fernandes RA , et al. A human IgSF cell-surface interactome reveals a complex network of proteinprotein interactions. Cell 2020; 182: 1027- 43.e17.

[27] Maynard JA , Lindquist NC , Sutherland JN , et al. Surface plasmon resonance for high-throughput ligand screening of membrane-bound proteins. Biotechnol J 2009; 4: 1542- 58.

[28] Deng M , Lu Z , Zheng J , et al. A motif in LILRB2 critical for Angptl2 binding and activation. Blood 2014; 124: 924- 35.

[29] Richardson MR , Robbins EP , Vemula S , et al. Angiopoietin-like protein 2 regulates endothelial colony forming cell vasculogenesis. Angiogenesis 2014; 17: 675- 83.

[30] Osumi H , Horiguchi H , Kadomatsu T , et al. Tumor cell-derived angiopoietin-like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells. Cancer Sci 2020; 111: 1241- 53.

[31] Wright GJ . Signal initiation in biological systems: the properties and detection of transient extracellular protein interactions. Mol Biosyst 2009; 5: 1405- 12.

[32] Wright GJ , Martin S , Bushell KM , et al. High-throughput identifcation of transient extracellular protein interactions. Biochem Soc Trans 2010; 38: 919- 22.

[33] Braun P , Tasan M , Dreze M , et al. An experimentally derived confdence score for binary protein-protein interactions. Nat Methods 2009; 6: 91- 7.

[34] Barrios-Rodiles M , Brown KR , Ozdamar B , et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 2005; 307: 1621- 5.

[35] Ramazi S , Zahiri J . Posttranslational modifcations in proteins: resources, tools and prediction methods. Database (Oxford) 2021; 2021: baab012.

[36] Ramazi S , Allahverdi A , Zahiri J . Evaluation of post-translational modifcations in histone proteins: a review on histone modifcation defects in developmental and neurological disorders. J Biosci 2020; 45: 135.

[37] Goddard AD , Watts A . Regulation of G protein-coupled receptors by palmitoylation and cholesterol. BMC Biol 2012; 10: 27.

[38] Becker PD , Royo JL , Guzman CA . Exploitation of prokaryotic expression systems based on the salicylate-dependent control circuit encompassing nahR/P(sal)::xylS2 for biotechnological applications. Bioeng Bugs 2010; 1: 244- 51.

[39] Brunk E , Chang RL , Xia J , et al. Characterizing posttranslational modifcations in prokaryotic metabolism using a multiscale workfow. Proc Natl Acad Sci USA 2018; 115: 11096- 101.

[40] Vizurraga A , Adhikari R , Yeung J , et al. Mechanisms of adhesion G protein-coupled receptor activation.J Biol Chem 2020; 295: 14065- 83.

[41] Bambakidis NC , Onwuzulike K . Chapter seventeen—sonic hedgehog signaling and potential therapeutic indications. In: Litwack G (ed.), Vitamins & Hormones, Vol. 88. San Diego: Academic Press, 2012, 379- 94.

[42] Joseph DB , Vezina CM . Male reproductive tract: development overview. In: Skinner MK (ed.), Encyclopedia of Reproduction. 2nd edn. Oxford: Academic Press, 2018, 248- 55.

[43] Araç D , Boucard AA , Bolliger MF , et al. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J 2012; 31: 1364- 78.

[44] Martinez-Martin N , Marcandalli J , Huang CS , et al. An unbiased screen for human cytomegalovirus identifes neuropilin-2 as a central viral receptor. Cell 2018; 174: 1158- 71.e19.

[45] Ozkan E , Carrillo RA , Eastman CL , et al. An extracellular interactome of immunoglobulin and LRR proteins reveals receptor-ligand networks. Cell 2013; 154: 228- 39.

[46] Bushell KM , Sollner C , Schuster-Boeckler B , et al. Large-scale screening for novel low-affinity extracellular protein interactions. Genome Res 2008; 18: 622- 30.

[47] Galaway F , Wright GJ . Rapid and sensitive large-scale screening of low affinity extracellular receptor protein interactions by using reaction induced inhibition of Gaussia luciferase. Sci Rep 2020; 10: 10522.

[48] Shilts J , Severin Y , Galaway F , et al. A physical wiring diagram for the human immune system. Nature 2022; 608: 397- 404.

[49] Ramachandran N , Raphael JV , Hainsworth E , et al. Next-generation high-density self-assembling functional protein arrays. Nat Methods 2008; 5: 535- 8.

[50] Tremblay TL , Hill JJ . Biotin-transfer from a trifunctional crosslinker for identifcation of cell surface receptors of soluble protein ligands. Sci Rep 2017; 7: 46574.

[51] Frei AP , Jeon OY , Kilcher S , et al. Direct identifcation of ligand-receptor interactions on living cells and tissues.Nat Biotechnol 2012; 30: 997- 1001.

[52] Coin I . Application of non-canonical crosslinking amino acids to study protein-protein interactions in live cells. Curr Opin Chem Biol 2018; 46: 156- 63.

[53] Pham ND , Parker RB , Kohler JJ . Photocrosslinking approaches to interactome mapping. Curr Opin Chem Biol 2013; 17: 90- 101.

[54] Frei AP , Moest H , Novy K , et al. Ligand-based receptor identifcation on living cells and tissues using TRICEPS. Nat Protoc 2013; 8: 1321- 36.

[55] Sobotzki N , Schafroth MA , Rudnicka A , et al. HATRIC-based identifcation of receptors for orphan ligands. Nat Commun 2018; 9: 1519.

[56] Yang Y , Song H , He D , et al. Genetically encoded releasable photocross-linking strategies for studying protein-protein interactions in living cells. Nat Protocols 2017; 12: 2147- 68.

[57] Roux KJ , Kim DI , Raida M , et al. A promiscuous biotin ligase fusion protein identifes proximal and interacting proteins in mammalian cells. J Cell Biol 2012; 196: 801- 10.

[58] Lobingier BT , Hüttenhain R , Eichel K , et al. An approach to spatiotemporally resolve protein interaction networks in living cells. Cell 2017; 169: 350- 60.e12.

[59] Kim DI , Jensen SC , Roux KJ . Identifying protein-protein associations at the nuclear envelope with BioID. Methods Mol Biol 2016; 1411: 133- 46.

[60] Bosch JA , Chen CL , Perrimon N . Proximity-dependent labeling methods for proteomic profling in living cells: an update. Wiley Interdisc Rev Dev Biol 2021; 10: e392.

[61] Lee SY , Kang MG , Park JS , et al. APEX fngerprinting reveals the subcellular localization of proteins of interest. Cell Rep 2016; 15: 1837- 47.

[62] Liu Q , Zheng J , Sun W , et al. A proximity-tagging system to identify membrane protein-protein interactions.Nat Methods 2018; 15: 715- 22.

[63] Lodes MJ , Dillon DC , Houghton RL , et al. Expression cloning. In: Decler J, Reischl U (eds.), Molecular Diagnosis of Infectious Diseases. Totowa, NJ: Humana Press, 2004, 91- 106.

[64] Pileri P , Uematsu Y , Campagnoli S , et al. Binding of hepatitis C virus to CD81. Science 1998; 282: 938- 41.

[65] Feng Y , Broder CC , Kennedy PE , et al. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272: 872- 7.

[66] Choe H , Farzan M , Sun Y , et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996; 85: 1135- 48.

[67] Nakayama N , Yokota T , Arai K . Use of mammalian cell expression cloning systems to identify genes for cytokines, receptors, and regulatory proteins. Curr Opin Biotechnol 1992; 3: 497- 505.

[68] Li S , Qian N , Jiang C , et al. Gain-of-function genetic screening identifes the antiviral function of TMEM120A via STING activation. Nat Commun 2022; 13: 105.

[69] Konermann S , Brigham MD , Trevino AE , et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 2015; 517: 583- 8.

[70] Gilbert LA , Horlbeck MA , Adamson B , et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell 2014; 159: 647- 61.

[71] Sharma S , Petsalaki E . Application of CRISPR-Cas9 based genomewide screening approaches to study cellular signalling mechanisms. Int J Mol Sci 2018; 19: 933.

[72] Gebre M , Nomburg JL , Gewurz BE . CRISPR-Cas9 genetic analysis of virus-host interactions. Viruses 2018; 10: 55.

[73] Sharma S , Wright GJ . Cell surface receptor identifcation using genome-scale CRISPR/Cas9 genetic screens. J Vis Exp 2020; 160: e60803.

[74] Chong ZS , Ohnishi S , Yusa K , et al. Pooled extracellular receptorligand interaction screening using CRISPR activation. Genome Biol 2018; 19: 205.

[75] Wang J , Sanmamed MF , Datar I , et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 2019; 176: 334- 47.e12.

[76] Yao S , Zhu Y , Zhu G , et al. B7-h2 is a costimulatory ligand for CD28 in human. Immunity 2011; 34: 729- 40.

[77] Zhu Y , Yao S , Iliopoulou BP , et al. B7-H5 costimulates human T cells via CD28H. Nat Commun 2013; 4: 2043.

[78] Lu Q , Liu J , Zhao S , et al. SARS-CoV-2 exacerbates proinfammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2. Immunity 2021; 54: 1304- 19.e9.

[79] Wang J , Sun J , Liu LN , et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med 2019; 25: 656- 66.

[80] Ozgul S , von Daake S , Kakehi S , et al. An ELISA-based screening platform for ligand-receptor discovery. Methods Enzymol 2019; 615: 453- 75.

[81] Crosnier C , Bustamante LY , Bartholdson SJ , et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 2011; 480: 534- 7.

[82] Martin S , Söllner C , Charoensawan V , et al. Construction of a large extracellular protein interaction network and its resolution by spatiotemporal expression profling. Mol Cell Proteomics 2010; 9: 2654- 65.

[83] Gao X , Metzger U , Panza P , et al. A foor-plate extracellular protein-protein interaction screen identifes draxin as a secreted netrin-1 antagonist. Cell Rep 2015; 12: 694- 708.

[84] Visser JJ , Cheng Y , Perry SC , et al. An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina. Elife 2015; 4: e08149.

[85] Söllner C , Wright GJA . cell surface interaction network of neural leucine-rich repeat receptors. Genome Biol 2009; 10: R99.

[86] Sun Y , Wright GJ . Detecting low-affinity extracellular protein interactions using protein microarrays. Curr Protoc Protein Sci 2013; Chapter 27: Unit 27.25.

[87] Tom I , Lewin-Koh N , Ramani SR , et al. Protein microarrays for identifcation of novel extracellular protein-protein interactions. Curr Protoc Protein Sci 2013; Chapter 27: Unit 27.23.

[88] Martinez-Martin N , Ramani SR , Hackney JA , et al. The extracellular interactome of the human adenovirus family reveals diverse strategies for immunomodulation. Nat Commun 2016; 7: 11473.

[89] Ramani SR , Tom I , Lewin-Koh N , et al. A secreted protein microarray platform for extracellular protein interaction discovery. Anal Biochem 2012; 420: 127- 38.

[90] Carlson ED , Gan R , Hodgman CE , et al. Cell-free protein synthesis: applications come of age. Biotechnol Adv 2012; 30: 1185- 94.

[91] Khan HS , Nair VR , Ruhl CR , et al. Identifcation of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis. Elife 2020; 9: e52551.

[92] Young DD , Schultz PG . Playing with the molecules of life. ACS Chem Biol 2018; 13: 854- 70.

[93] Pless SA , Ahern CA . Unnatural amino acids as probes of ligandreceptor interactions and their conformational consequences. Annu Rev Pharmacol Toxicol 2013; 53: 211- 29.

[94] Seidel L , Coin I . Mapping of protein interfaces in live cells using genetically encoded crosslinkers. Methods Mol Biol 2018; 1728: 221- 35.

[95] Zhang M , Lin S , Song X , et al. A genetically incorporated crosslinker reveals chaperone cooperation in acid resistance. Nat Chem Biol 2011; 7: 671- 7.

[96] Lakshmipathy SK , Tomic S , Kaiser CM , et al. Identifcation of nascent chain interaction sites on trigger factor. J Biol Chem 2007; 282: 12186- 93.

[97] Han S , Collins BE , Bengtson P , et al. Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking. Nat Chem Biol 2005; 1: 93- 7.

[98] Coin I , Perrin MH , Vale WW , et al. Photo-cross-linkers incorporated into G-protein-coupled receptors in mammalian cells: a ligand comparison. Angew Chem Int Ed Engl 2011; 50: 8077- 81.

[99] Coin I , Katritch V , Sun T , et al. Genetically encoded chemical probes in cells reveal the binding path of urocortin-I to CRF class B GPCR. Cell 2013; 155: 1258- 69.

[100] Mori H , Ito K . Different modes of SecY-SecA interactions revealed by site-directed in vivo photo-cross-linking. Proc Natl Acad Sci U S A 2006; 103: 16159- 64.

[101] Okuda S , Freinkman E , Kahne D . Cytoplasmic ATP hydrolysis powers transport of lipopolysaccharide across the periplasm in E. coli. Science 2012; 338: 1214- 7.

[102] Zapatero-Belinchón FJ , Carriquí-Madroñal B , Gerold G . Proximity labeling approaches to study protein complexes during virus infection. Adv Virus Res 2021; 109: 63- 104.

[103] Rucks EA , Olson MG , Jorgenson LM , et al. Development of a proximity labeling system to map the Chlamydia trachomatis inclusion membrane. Front Cell Infect Microbiol 2017; 7: 40.

[104] Dickinson MS , Anderson LN , Webb-Robertson BM , et al. Proximity-dependent proteomics of the Chlamydia trachomatis inclusion membrane reveals functional interactions with endoplasmic reticulum exit sites. PLoS Pathog 2019; 15: e1007698.

[105] Olson MG , Widner RE , Jorgenson LM , et al. Proximity labeling to map host-pathogen interactions at the membrane of a bacterium-containing vacuole in chlamydia trachomatis-infected human cells. Infect Immun 2019; 87: e00537- 19.

[106] Samavarchi-Tehrani P , Abdouni H , Knight JDR , et al. A SARS-CoV-2—host proximity interactome. bioRxiv, 4 September 2020, preprint: not peer reviewed.

[107] Ritchie C , Cylinder I , Platt EJ , et al. Analysis of HIV-1 Gag protein interactions via biotin ligase tagging. J Virol 2015; 89: 3988- 4001.

[108] Coyaud E , Ranadheera C , Cheng D , et al. Global interactomics uncovers extensive organellar targeting by Zika virus. Mol Cell Proteomics 2018; 17: 2242- 55.

[109] Chen J , Fan J , Chen Z , et al. Nonmuscle myosin heavy chain IIA facilitates SARS-CoV-2 infection in human pulmonary cells. Proc Natl Acad Sci U S A 2021; 118: e2111011118.

[110] Strack R . Revealing the secretome.Nat Methods 2021; 18: 1273- 1273.

[111] Kim K-E , Park I , Kim J , et al. Dynamic tracking and identifcation of tissue-specifc secretory proteins in the circulation of live mice. Nat Commun 2021; 12: 5204.

[112] Droujinine IA , Meyer AS , Wang D , et al. Proteomics of protein trafficking by in vivo tissue-specifc labeling. Nat Commun 2021; 12: 2382.

[113] Wei W , Riley NM , Yang AC , et al. Cell type-selective secretome profling in vivo. Nat Chem Biol 2021; 17: 326- 34.

[114] Liu J , Jang JY , Pirooznia M , et al. The secretome mouse provides a genetic platform to delineate tissue-specifc in vivo secretion. Proc Natl Acad Sci USA 2021; 118: e2005134118.

[115] Murray MJ , Cunningham JM , Parada LF , et al. The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. Cell 1983; 33: 749- 57.

[116] Evans MJ , von Hahn T , Tscherne DM , et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 2007; 446: 801- 5.

[117] Ploss A , Evans MJ , Gaysinskaya VA , et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 2009; 457: 882- 6.

[118] Davis S , Gale NW , Aldrich TH , et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 1994; 266: 816- 9.

[119] Lin HY , Wang XF , Ng-Eaton E , et al. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell 1992; 68: 775- 85.

[120] Mathews LS , Vale WW . Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 1991; 65: 973- 82.

[121] Bianchi E , Doe B , Goulding D , et al. Juno is the egg Izumo receptor and is essential for mammalian fertilization. Nature 2014; 508: 483- 7.

[122] Cong L , Ran FA , Cox D , et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339: 819- 23.

[123] Mali P , Yang L , Esvelt KM , et al. RNA-guided human genome engineering via Cas9. Science 2013; 339: 823- 6.

[124] Qi LS , Larson MH , Gilbert LA , et al. Repurposing CRISPR as an RNA-guided platform for sequence-specifc control of gene expression. Cell 2013; 152: 1173- 83.

[125] Puschnik AS , Majzoub K , Ooi YS , et al. A CRISPR toolbox to study virus-host interactions. Nat Rev Microbiol 2017; 15: 351- 64.

[126] Orchard RC , Wilen CB , Doench JG , et al. Discovery of a proteinaceous cellular receptor for a norovirus. Science 2016; 353: 933- 6.

[127] Wu K , Oberstein A , Wang W , et al. Role of PDGF receptor-α during human cytomegalovirus entry into fbroblasts. Proc Natl Acad Sci U S A 2018; 115: E9889- 98.

[128] Xiaofei E , Meraner P , Lu P , et al. OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defnes viral epithelial cell tropism. Proc Natl Acad Sci U S A 2019; 116: 7043- 52.

[129] Haga K , Fujimoto A , Takai-Todaka R , et al. Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells. Proc Natl Acad Sci U S A 2016; 113: E6248- 55.

[130] Ma H , Kim AS , Kafai NM , et al. LDLRAD3 is a receptor for Venezuelan equine encephalitis virus. Nature 2020; 588: 308- 14.

[131] Marceau CD , Puschnik AS , Majzoub K , et al. Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens. Nature 2016; 535: 159- 63.

[132] Wang R , Simoneau CR , Kulsuptrakul J , et al. Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses. Cell 2021; 184: 106- 19.e14.

[133] Zhu Y , Feng F , Hu G , et al. A genome-wide CRISPR screen identifes host factors that regulate SARS-CoV-2 entry. Nat Commun 2021; 12: 961.

[134] Schneider WM , Luna JM , Hoffmann HH , et al. Genome-scale identifcation of SARS-CoV-2 and Pan-coronavirus host factor networks. Cell 2021; 184: 120- 32.e14.

[135] Daniloski Z , Jordan TX , Wessels HH , et al. Identifcation of required host factors for SARS-CoV-2 infection in human cells. Cell 2021; 184: 92- 105.e16.

[136] Siepe DH , Henneberg LT , Wilson SC , et al. Identifcation of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform. Elife 2022; 11: e81398.

[137] Wei J , Alfajaro MM , DeWeirdt PC , et al. Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection. Cell 2021; 184: 76- 91.e13.

[138] Mezzadra R , Sun C , Jae LT , et al. Identifcation of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature 2017; 549: 106- 10.

[139] Burr ML , Sparbier CE , Chan YC , et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature 2017; 549: 101- 5.

[140] Sharma S , Bartholdson SJ , Couch ACM , et al. Genome-scale identifcation of cellular pathways required for cell surface recognition. Genome Res 2018; 28: 1372- 82.

[141] Wood L , Wright GJ . High-content imaging for large-scale detection of low-affinity extracellular protein interactions. SLAS Discov 2019; 24: 987- 99.

[142] Zhu Y , Yao S , Augustine MM , et al. Neuron-specifc SALM5 limits infammation in the CNS via its interaction with HVEM. Sci Adv 2016; 2: e1500637.

[143] Lu N , Li Y , Zhang Z , et al. Human semaphorin-4A drives Th2 responses by binding to receptor ILT-4. Nat Commun 2018; 9: 742.

[144] Bazzone LE , King M , MacKay CR , et al. A Disintegrin and Metalloproteinase 9 Domain (ADAM9) is a major susceptibility factor in the early stages of encephalomyocarditis virus infection. Mbio 2019; 10: e02734- 18.

[145] Ziauddin J , Sabatini DM . Microarrays of cells expressing defned cDNAs. Nature 2001; 411: 107- 10.

[146] Mullican SE , Lin-Schmidt X , Chin CN , et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 2017; 23: 1150- 7.

[147] Turner L , Lavstsen T , Berger SS , et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 2013; 498: 502- 5.

[148] Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252- 64.

[149] Crowther MD , Dolton G , Legut M , et al. Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat Immunol 2020; 21: 178- 85.

[150] Jiang P , Lagenaur CF , Narayanan V . Integrin-associated protein is a ligand for the P84 neural adhesion molecule. J Biol Chem 1999; 274: 559- 62.

[151] Lyman SD , James L , Vanden Bos T , et al. Molecular cloning of a ligand for the ft3/fk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75: 1157- 67.

[152] Zheng J , Umikawa M , Cui C , et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 2012; 485: 656- 60.

[153] Jequier E . Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 2002; 967: 379- 88.

[154] Hsu JY , Crawley S , Chen M , et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 2017; 550: 255- 9.

[155] Thorens B . Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A 1992; 89: 8641- 5.

[156] Wang Y , Szretter KJ , Vermi W , et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 2012; 13: 753- 60.

[157] Mao X , Ou MT , Karuppagounder SS , et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016; 353: aah3374.

[158] Yeh FL , Wang Y , Tom I , et al. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 2016; 91: 328- 40.

[159] Lin JC , Ho WH , Gurney A , et al. The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons. Nat Neurosci 2003; 6: 1270- 6.

[160] Okabe M . Sperm-egg interaction and fertilization: past, present, and future. Biol Reprod 2018; 99: 134- 46.

[161] Reinhart J , Mertz LM , Catt KJ . Molecular cloning and expression of cDNA encoding the murine gonadotropin-releasing hormone receptor. J Biol Chem 1992; 267: 21281- 4.

[162] Bianchi E , Sun Y , Almansa-Ordonez A , et al. Control of oviductal fuid fow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit. Nat Commun 2021; 12: 1251.

[163] Nicod C , Banaei-Esfahani A , Collins BC . Elucidation of hostpathogen protein-protein interactions to uncover mechanisms of host cell rewiring. Curr Opin Microbiol 2017; 39: 7- 15.

[164] Au EYL , Tung EKK , Ip RWK , et al. Novel MAGT1 mutation found in the frst Chinese XMEN in Hong Kong. Case Reports Immunol 2022; 2022: 2390167.

[165] Dragic T , Litwin V , Allaway GP , et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381: 667- 73.

[166] Liu Y , Liu H , Kim BO , et al. CD4-independent infection of astrocytes by human immunodefciency virus type 1: requirement for the human mannose receptor. J Virol 2004; 78: 4120- 33.

[167] Vogtle T , Sharma S , Mori J , et al. Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. Elife 2019; 8: e46840.

[168] Hart TM , Sonnert ND , Tang X , et al. An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms. Cell 2024; 187: 4113- 27.e13.

[169] Balloux F , van Dorp L . Q&A: what are pathogens, and what have they done to and for us? BMC Biol 2017; 15: 91.

[170] Barrass SV , Butcher SJ . Advances in high-throughput methods for the identifcation of virus receptors. Med Microbiol Immunol 2020; 209: 309- 23.

[171] Dundas K , Shears MJ , Sun Y , et al. Alpha-v-containing integrins are host receptors for the Plasmodium falciparum sporozoite surface protein, TRAP. Proc Natl Acad Sci U S A 2018; 115: 4477- 82.

[172] Bartholdson SJ , Crosnier C , Bustamante LY , et al. Identifying novel Plasmodium falciparum erythrocyte invasion receptors using systematic extracellular protein interaction screens. Cell Microbiol 2013; 15: 1304- 12.

[173] Margarit I , Bonacci S , Pietrocola G , et al. Capturing host-pathogen interactions by protein microarrays: identifcation of novel streptococcal proteins binding to human fbronectin, fbrinogen, and C4BP. FASEB J 2009; 23: 3100- 12.

[174] Zhang R , Kim AS , Fox JM , et al. Mxra8 is a receptor for multiple arthritogenic alphaviruses. Nature 2018; 557: 570- 4.

[175] Zhang R , Earnest JT , Kim AS , et al. Expression of the Mxra8 receptor promotes alphavirus infection and pathogenesis in mice and Drosophila. Cell Rep 2019; 28: 2647- 58.e5.

[176] Savidis G , McDougall WM , Meraner P , et al. Identifcation of Zika virus and dengue virus dependency factors using functional genomics. Cell Rep 2016; 16: 232- 46.

[177] Wang S , Zhang Q , Tiwari SK , et al. Integrin alphavbeta5 internalizes Zika virus during neural stem cells infection and provides a promising target for antiviral therapy. Cell Rep 2020; 30: 969- 83.e4.

[178] Karakus U , Thamamongood T , Ciminski K , et al. MHC class II proteins mediate cross-species entry of bat infuenza viruses. Nature 2019; 567: 109- 12.

[179] Sosnovtsev SV , Sandoval-Jaime C , Parra GI , et al. Identifcation of human junctional adhesion molecule 1 as a functional receptor for the Hom-1 calicivirus on human cells. Mbio 2017; 8: e00031- 17.

[180] Chen J , Zhao Y , Zhang C , et al. Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res 2014; 24: 1050- 66.

[181] Kim AS , Zimmerman O , Fox JM , et al. An evolutionary insertion in the Mxra8 receptor-binding site confers resistance to alphavirus infection and pathogenesis. Cell Host Microbe 2020; 27: 428- 40.e9.

[182] Shue B , Chiramel AI , Cerikan B , et al. Genome-wide CRISPR screen identifes RACK1 as a critical host factor for favivirus replication. J Virol 2021; 95: e0059621.

[183] Shilts J , Crozier TWM , Teixeira-Silva A , et al. LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein. PLoS Biol 2023; 21: e3001959.

[184] Horwitz DA , Fahmy TM , Piccirillo CA , et al. Rebalancing immune homeostasis to treat autoimmune diseases. Trends Immunol 2019; 40: 888- 908.

[185] Jiang X , Wang J , Deng X , et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer 2019; 18: 10- 10.

[186] So AK , Martinon F . Infammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol 2017; 13: 639- 47.

[187] Kraehenbuehl L , Weng CH , Eghbali S , et al. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol 2021; 19: 37- 50.

[188] Wang J , Wu G , Manick B , et al. VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology 2019; 156: 74- 85.

[189] Johnston RJ , Su LJ , Pinckney J , et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature 2019; 574: 565- 70.

[190] Yuan L , Tatineni J , Mahoney KM , et al. VISTA: a mediator of quiescence and a promising target in cancer immunotherapy. Trends Immunol 2021; 42: 209- 27.

[191] Husain B , Ramani SR , Chiang E , et al. A platform for extracellular interactome discovery identifes novel functional binding partners for the immune receptors B7-H3/CD276 and PVR/CD155. Mol Cell Proteomics 2019; 18: 2310- 23.

[192] Verschueren E , Husain B , Yuen K , et al. The immunoglobulin superfamily receptome defnes cancer-relevant networks associated with clinical outcome. Cell 2020; 182: 329- 44.e19.

[193] Goodwin RG , Din WS , Davis-Smith T , et al. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur J Immunol 1993; 23: 2631- 41.

[194] Marin-Acevedo JA , Dholaria B , Soyano AE , et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol 2018; 11: 39- 39.

[195] Spriggs MK , Armitage RJ , Strockbine L , et al. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med 1992; 176: 1543- 50.

[196] Vonderheide RH . CD40 Agonist antibodies in cancer immunotherapy. Annu Rev Med 2020; 71: 47- 58.

[197] Zhu C , Anderson AC , Schubart A , et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005; 6: 1245- 52.

[198] Burugu S , Dancsok AR , Nielsen TO . Emerging targets in cancer immunotherapy. Semin Cancer Biol 2018; 52: 39- 52.

[199] Klein K , Hölzemer A , Wang T , et al. A genome-wide CRISPR/Cas9-based screen identifes heparan sulfate proteoglycans as ligands of killer-cell immunoglobulin-like receptors. Front Immunol 2021; 12: 798235.

[200] Kamber RA , Nishiga Y , Morton B , et al. Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis. Nature 2021; 597: 549- 54.

[201] Maruhashi T , Sugiura D , Okazaki IM , et al. LAG-3: from molecular functions to clinical applications. J ImmunoTher Cancer 2020; 8: e001014.

[202] Sun J , Lu Q , Sanmamed MF , et al. Siglec-15 as an emerging target for next-generation cancer immunotherapy. Clin Cancer Res 2021; 27: 680- 8.

[203] Fan XZ , Quezada SA , Sepulveda MA , et al. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med 2014; 211: 715- 25.

[204] Zheng L , Han X , Yao S , et al. The CD8α-PILRα interaction maintains CD8+ T cell quiescence. Science 2022; 376: 996- 1001.

[205] Mullard A . FDA approves 100th monoclonal antibody product. Nat Rev Drug Discov 2021; 20: 491- 5.

[206] Lambrecht BN , Hammad H , Fahy JV . The cytokines of asthma. Immunity 2019; 50: 975- 91.

[207] Li M , Wang Y , Li M , et al. Integrins as attractive targets for cancer therapeutics. Acta Pharm Sin B 2021; 11: 2726- 37.

[208] Sandborn WJ , Hanauer SB , Katz S , et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121: 1088- 94.

[209] Arteaga CL , Sliwkowski MX , Osborne CK , et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2011; 9: 16- 32.

[210] Yi M , Jiao D , Xu H , et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 2018; 17: 129.

[211] Nguyen LT , Ohashi PS . Clinical blockade of PD1 and LAG3-potential mechanisms of action. Nat Rev Immunol 2015; 15: 45- 56.

[212] Huang X , Zhang X , Li E , et al. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol 2020; 13: 83.

[213] Lines JL , Sempere LF , Broughton T , et al. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2014; 2: 510- 7.

[214] Astarita JL , Keerthivasan S , Husain B , et al. The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fbroblast physiology. PLoS One 2021; 16: e0260800.

[215] Muntasell A , Ochoa MC , Cordeiro L , et al. Targeting NK-cell checkpoints for cancer immunotherapy. Curr Opin Immunol 2017; 45: 73- 81.

[216] Perez-Ruiz E , Etxeberria I , Rodriguez-Ruiz ME , et al. Anti-CD137 and PD-1/PD-L1 antibodies En route toward clinical synergy. Clin Cancer Res 2017; 23: 5326- 8.

[217] Cabo M , Offringa R , Zitvogel L , et al. Trial watch: immunostimulatory monoclonal antibodies for oncological indications. Oncoimmunology 2017; 6: e1371896.

[218] Baum PR , Gayle Iii RB , Ramsdell F , et al. Molecular characterization of murine and human OX40/OX40 ligand systems: identifcation of a human OX40 ligand as the HTLV-1-regulated protein gp34. EMBO J 1994; 13: 3992- 4001.

[219] Curti BD , Kovacsovics-Bankowski M , Morris N , et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 2013; 73: 7189- 98.

[220] Sikic BI , Lakhani N , Patnaik A , et al. First-in-human, frst-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J Clin Oncol 2019; 37: 946- 53.

[221] Butte MJ , Keir ME , Phamduy TB , et al. Programmed death-1 ligand 1 interacts specifcally with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27: 111- 22.

[222] Migden MR , Rischin D , Schmults CD , et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018; 379: 341- 51.

[223] Brignone C , Gutierrez M , Mefti F , et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med 2010; 8: 71.

[224] Kojima Y , Volkmer JP , McKenna K , et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 2016; 536: 86- 90.

[225] Wernig G , Chen SY , Cui L , et al. Unifying mechanism for different fbrotic diseases. Proc Natl Acad Sci U S A 2017; 114: 4757- 62.

[226] Durcan L , O’Dwyer T , Petri M . Management strategies and future directions for systemic lupus erythematosus in adults. Lancet 2019; 393: 2332- 43.

[227] Vincent FB , Morand EF , Schneider P , et al. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol 2014; 10: 365- 73.

[228] Rabinovitch M , Guignabert C , Humbert M , et al. Infammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115: 165- 75.

[229] Hill BD , Zak A , Khera E , et al. Engineering virus-like particles for antigen and drug delivery. Curr Protein Pept Sci 2018; 19: 112- 27.

[230] Nooraei S , Bahrulolum H , Hoseini ZS , et al. Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers. J Nanobiotechnology 2021; 19: 59- 59.

[231] Roldão A , Mellado MC , Castilho LR , et al. Virus-like particles in vaccine development. Expert Rev Vaccines 2010; 9: 1149- 76.

[232] Zepeda-Cervantes J , Ramírez-Jarquín JO , Vaca L . Interaction between Virus-Like Particles (VLPs) and Pattern Recognition Receptors (PRRs) from Dendritic Cells (DCs): Toward Better Engineering of VLPs. Front Immunol 2020; 11: 1100.

[233] Syu G-D , Wang S-C , Ma G , et al. Development and application of a high-content virion display human GPCR array. Nat Commun 2019; 10: 1997.

[234] Ho TT , Nguyen JT , Liu J , et al. Method for rapid optimization of recombinant GPCR protein expression and stability using virus-like particles. Protein Expr Purif 2017; 133: 41- 9.

[235] Dodd R , Schofeld DJ , Wilkinson T , et al. Generating therapeutic monoclonal antibodies to complex multi-spanning membrane targets: overcoming the antigen challenge and enabling discovery strategies. Methods 2020; 180: 111- 26.

[236] Jiang Y , Wang D , Wang W , et al. Computational methods for protein localization prediction.Comput Struct Biotechnol J 2021; 19: 5834- 44.

[237] Petersen TN , Brunak S , von Heijne G , et al. SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods 2011; 8: 785- 6.

[238] Kall L , Krogh A , Sonnhammer EL . Advantages of combined transmembrane topology and signal peptide prediction—the Phobius web server. Nucleic Acids Res 2007; 35: W429- 432.

[239] Viklund H , Bernsel A , Skwark M , et al. SPOCTOPUS: a combined predictor of signal peptides and membrane protein topology. Bioinformatics 2008; 24: 2928- 9.

[240] Cohen MJ , Chirico WJ , Lipke PN . Through the back door: unconventional protein secretion. Cell Surf 2020; 6: 100045.

[241] Duitman EH , Orinska Z , Bulfone-Paus S . Mechanisms of cytokine secretion: a portfolio of distinct pathways allows fexibility in cytokine activity. Eur J Cell Biol 2011; 90: 476- 83.

[242] Efremova M , Vento-Tormo M , Teichmann SA , et al. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc 2020; 15: 1484- 506.

[243] Armingol E , Officer A , Harismendy O , et al. Deciphering cell-cell interactions and communication from gene expression. Nat Rev Genet 2021; 22: 71- 88.

[244] Shilts J , Wright GJ . Mapping the human cell surface interactome: a key to decode cell-to-cell communication. Annu Rev Biomed Data Sci 2024; 7: 155- 77.

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