Regulation of NLR stability in plant immunity

Abstract

Plant nucleotide binding domain and leucine-rich repeat (NLR) receptors recognize pathogen effectors directly or indirectly and mediate innate immune responses. NLR-mediated immunity also has direct impacts on plant growth and development, as well as yield and survival. The levels of NLR proteins are therefore intricately controlled in plants to balance defense responses and other processes. In recent years, the ubiquitination-26S proteasome system and the HSP90 chaperones have emerged as having key functions in the regulation of NLR stability. The N-end rule pathway of protein degradation is also directly linked to NLR stability. Recent progress in the regulation of NLR stability and turnover is summarized here, focusing on the key components and pathways.

Keywords

E3 ubiquitin ligase / degradation / nucleotide-binding leucine-rich repeat receptor / plant immunity / proteasome / protein stability / ubiquitination

References

[1] Dangl J L, Horvath D M, Staskawicz B J. Pivoting the plant immune system from dissection to deployment. Science, 2013, 341(6147): 746–751

[2] Zipfel C. Plant pattern-recognition receptors. Trends in Immunology, 2014, 35(7): 345–351

[3] Dodds P N, Rathjen J P. Plant immunity: towards an integrated view of plant-pathogen interactions. Nature Reviews: Genetics, 2010, 11(8): 539–548

[4] Jones J D, Vance R E, Dangl J L. Intracellular innate immune surveillance devices in plants and animals. Science, 2016, 354(6316): aaf6395

[5] Cook D E, Mesarich C H, Thomma B P. Understanding plant immunity as a surveillance system to detect invasion. Annual Review of Phytopathology, 2015, 53(1): 541–563

[6] Tsuda K, Katagiri F. Comparing signaling mechanisms engaged in pattern-triggered and effector-triggered immunity. Current Opinion in Plant Biology, 2010, 13(4): 459–465

[7] Tsuda K, Mine A, Bethke G, Igarashi D, Botanga C J, Tsuda Y, Glazebrook J, Sato M, Katagiri F. Dual regulation of gene expression mediated by extended MAPK activation and salicylic acid contributes to robust innate immunity in Arabidopsis thaliana. PLOS Genetics, 2013, 9(12): e1004015

[8] Jacob F, Vernaldi S, Maekawa T. Evolution and conservation of plant NLR functions. Frontiers in Immunology, 2013, 4: e297

[9] Cui H, Tsuda K, Parker J E. Effector-triggered immunity: from pathogen perception to robust defense. Annual Review of Phytopathology, 2015, 66(1): 487–511

[10] Chae E, Bomblies K, Kim S T, Karelina D, Zaidem M, Ossowski S, Martín-Pizarro C, Laitinen R A E, Rowan B A, Tenenboim H, Lechner S, Demar M, Habring-Müller A, Lanz C, Rätsch G, Weigel D. Species-wide genetic incompatibility analysis identifies immune genes as hot spots of deleterious epistasis. Cell, 2014, 159(6): 1341–1351

[11] Cheng Y T, Li Y, Huang S, Huang Y, Dong X, Zhang Y, Li X. Stability of plant immune-receptor resistance proteins is controlled by SKP1-CULLIN1-F-box (SCF)-mediated protein degradation. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(35): 14694–14699

[12] Rodriguez E, El Ghoul H, Mundy J, Petersen M. Making sense of plant autoimmunity and ‘negative regulators’. FEBS Journal, 2016, 283(8): 1385–1391

[13] Cheng Y T, Li X. Ubiquitination in NB-LRR-mediated immunity. Current Opinion in Plant Biology, 2012, 15(4): 392–399

[14] Li X, Kapos P, Zhang Y. NLRs in plants. Current Opinion in Immunology, 2015, 32: 114–121

[15] Shirasu K. The HSP90-SGT1 chaperone complex for NLR immune sensors. Annual Review of Plant Biology, 2009, 60(1): 139–164

[16] Pickart C M, Eddins M J. Ubiquitin: structures, functions, mechanisms. Biochimica et Biophysica Acta, 2004, 1695(1–3): 55–72

[17] Smalle J, Vierstra R D. The ubiquitin 26S proteasome proteolytic pathway. Annual Review of Plant Biology, 2004, 55(1): 555–590

[18] Vierstra R D. The ubiquitin-26S proteasome system at the nexus of plant biology. Nature Reviews: Molecular Cell Biology, 2009, 10(6): 385–397

[19] Hoppe T. Multiubiquitylation by E4 enzymes: ‘one size’ doesn’t fit all. Trends in Biochemical Sciences, 2005, 30(4): 183–187

[20] Trujillo M. News from the PUB: plant U-box type E3 ubiquitin ligases. Journal of Experimental Botany, 2018, 69(3): 371–384

[21] Isono E, Katsiarimpa A, Müller I K, Anzenberger F, Stierhof Y D, Geldner N, Chory J, Schwechheimer C. The deubiquitinating enzyme AMSH3 is required for intracellular trafficking and vacuole biogenesis in Arabidopsis thaliana. Plant Cell, 2010, 22(6): 1826–1837

[22] Varshavsky A. The N-end rule pathway and regulation by proteolysis. Protein Science, 2011, 20(8): 1298–1345

[23] Mogk A, Schmidt R, Bukau B. The N-end rule pathway for regulated proteolysis: prokaryotic and eukaryotic strategies. Trends in Cell Biology, 2007, 17(4): 165–172

[24] Gibbs D J, Lee S C, Md Isa N, Gramuglia S, Fukao T, Bassel G W, Correia C S, Corbineau F, Theodoulou F L, Bailey-Serres J, Holdsworth M J. Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants. Nature, 2011, 479(7373): 415–418

[25] Gibbs D J, Bailey M, Tedds H M, Holdsworth M J. From start to finish: amino-terminal protein modifications as degradation signals in plants. New Phytologist, 2016, 211(4): 1188–1194

[26] Bachmair A, Finley D, Varshavsky A. In vivo half-life of a protein is a function of its amino-terminal residue. Science, 1986, 234(4773): 179–186

[27] Gou M, Shi Z, Zhu Y, Bao Z, Wang G, Hua J. The F-box protein CPR1/CPR30 negatively regulates R protein SNC1 accumulation. Plant Journal, 2012, 69(3): 411–420

[28] Li X, Clarke J D, Zhang Y, Dong X. Activation of an EDS1-mediated R-gene pathway in the snc1 mutant leads to constitutive, NPR1-independent pathogen resistance. Molecular Plant-Microbe Interactions, 2001, 14(10): 1131–1139

[29] Kroj T, Chanclud E, Michel-Romiti C, Grand X, Morel J B. Integration of decoy domains derived from protein targets of pathogen effectors into plant immune receptors is widespread. New Phytologist, 2016, 210(2): 618–626

[30] Dong O X, Ao K, Xu F, Johnson K C M, Wu Y, Li L, Xia S, Liu Y, Huang Y, Rodriguez E, Chen X, Chen S, Zhang Y, Petersen M, Li X. Individual components of paired typical NLR immune receptors are regulated by distinct E3 ligases. Nature Plants, 2018, 4(9): 699–710

[31] Li W, Wang B, Wu J, Lu G, Hu Y, Zhang X, Zhang Z, Zhao Q, Feng Q, Zhang H, Wang Z, Wang G, Han B, Wang Z, Zhou B. The Magnaporthe oryzae avirulence gene AvrPiz-t encodes a predicted secreted protein that triggers the immunity in rice mediated by the blast resistance gene Piz-t. Molecular Plant-Microbe Interactions, 2009, 22(4): 411–420

[32] Zhou B, Qu S, Liu G, Dolan M, Sakai H, Lu G, Bellizzi M, Wang G L. The eight amino-acid differences within three leucine-rich repeats between Pi2 and Piz-t resistance proteins determine the resistance specificity to Magnaporthe grisea. Molecular Plant-Microbe Interactions, 2006, 19(11): 1216–1228

[33] Park C H, Shirsekar G, Bellizzi M, Chen S, Songkumarn P, Xie X, Shi X, Ning Y, Zhou B, Suttiviriya P, Wang M, Umemura K, Wang G L. The E3 ligase APIP10 connects the effector AvrPiz-t to the NLR receptor piz-t in rice. PLOS Pathogens, 2016, 12(3): e1005529

[34] Park C H, Chen S, Shirsekar G, Zhou B, Khang C H, Songkumarn P, Afzal A J, Ning Y, Wang R, Bellizzi M, Valent B, Wang G L. The Magnaporthe oryzae effector AvrPiz-t targets the RING E3 ubiquitin ligase APIP6 to suppress pathogen-associated molecular pattern-triggered immunity in rice. Plant Cell, 2012, 24(11): 4748–4762

[35] Seeholzer S, Tsuchimatsu T, Jordan T, Bieri S, Pajonk S, Yang W, Jahoor A, Shimizu K K, Keller B, Schulze-Lefert P. Diversity at the Mla powdery mildew resistance locus from cultivated barley reveals sites of positive selection. Molecular Plant-Microbe Interactions, 2010, 23(4): 497–509

[36] Wang T, Chang C, Gu C, Tang S, Xie Q, Shen Q H. An E3 ligase affects the NLR receptor stability and immunity to Powdery Mildew. Plant Physiology, 2016, 172(4): 2504–2515

[37] van Wersch R, Li X, Zhang Y. Mighty Dwarfs: Arabidopsis autoimmune mutants and their usages in genetic dissection of plant immunity. Frontiers of Plant Science, 2016, 7: 1717

[38] Huang Y, Minaker S, Roth C, Huang S, Hieter P, Lipka V, Wiermer M, Li X. An E4 ligase facilitates polyubiquitination of plant immune receptor resistance proteins in Arabidopsis. Plant Cell, 2014, 26(1): 485–496

[39] Copeland C, Woloshen V, Huang Y, Li X. AtCDC48A is involved in the turnover of an NLR immune receptor. Plant Journal, 2016, 88(2): 294–305

[40] Baek G H, Kim I, Rao H. The Cdc48 ATPase modulates the interaction between two proteolytic factors Ufd2 and Rad23. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(33): 13558–13563

[41] Barthelme D, Chen J Z, Grabenstatter J, Baker T A, Sauer R T. Architecture and assembly of the archaeal Cdc48·20S proteasome. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(17): E1687–E1694

[42] Chung J Y, Park Y C, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. Journal of Cell Science, 2002, 115(4): 679–688

[43] Xie P. TRAF molecules in cell signaling and in human diseases. Journal of Molecular Signaling, 2013, 8(1): 7

[44] Oelmüller R, Peškan-Berghöfer T, Shahollari B, Trebicka A, Sherameti I, Varma A. MATH domain proteins represent a novel protein family in Arabidopsis thaliana, and at least one member is modified in roots during the course of a plant-microbe interaction. Physiologia Plantarum, 2005, 124(2): 152–166

[45] Huang S, Chen X, Zhong X, Li M, Ao K, Huang J, Li X. Plant TRAF proteins regulate NLR immune receptor turnover. Cell Host & Microbe, 2016, 19(2): 204–215

[46] Huang J, Zhu C, Li X. SCF^SNIPER4 controls the turnover of two redundant TRAF proteins in plant immunity. Plant Journal, 2018, 95(3): 504–515

[47] Hwang C S, Shemorry A, Auerbach D, Varshavsky A. The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases. Nature Cell Biology, 2010, 12(12): 1177–1185

[48] Hwang C S, Shemorry A, Varshavsky A. N-terminal acetylation of cellular proteins creates specific degradation signals. Science, 2010, 327(5968): 973–977

[49] Lee K E, Heo J E, Kim J M, Hwang C S. N-terminal acetylation-targeted N-end rule proteolytic system: the Ac/N-end rule pathway. Molecules and Cells, 2016, 39(3): 169–178

[50] Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, Varhaug J E, Vandekerckhove J, Lillehaug J R, Sherman F, Gevaert K. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(20): 8157–8162

[51] Starheim K K, Gevaert K, Arnesen T. Protein N-terminal acetyltransferases: when the start matters. Trends in Biochemical Sciences, 2012, 37(4): 152–161

[52] Xu F, Huang Y, Li L, Gannon P, Linster E, Huber M, Kapos P, Bienvenut W, Polevoda B, Meinnel T, Hell R, Giglione C, Zhang Y, Wirtz M, Chen S, Li X. Two N-terminal acetyltransferases antagonistically regulate the stability of a nod-like receptor in Arabidopsis. Plant Cell, 2015, 27(5): 1547–1562

[53] Pearl L H, Prodromou C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annual Review of Biochemistry, 2006, 75(1): 271–294

[54] Kadota Y, Shirasu K. The HSP90 complex of plants. Biochimica et Biophysica Acta, 2012, 1823(3): 689–697

[55] van Ooijen G, Mayr G, Kasiem M M, Albrecht M, Cornelissen B J, Takken F L. Structure-function analysis of the NB-ARC domain of plant disease resistance proteins. Journal of Experimental Botany, 2008, 59(6): 1383–1397

[56] Lu R, Malcuit I, Moffett P, Ruiz M T, Peart J, Wu A J, Rathjen J P, Bendahmane A, Day L, Baulcombe D C. High throughput virus-induced gene silencing implicates heat shock protein 90 in plant disease resistance. EMBO Journal, 2003, 22(21): 5690–5699

[57] Hubert D A, Tornero P, Belkhadir Y, Krishna P, Takahashi A, Shirasu K, Dangl J L. Cytosolic HSP90 associates with and modulates the Arabidopsis RPM1 disease resistance protein. EMBO Journal, 2003, 22(21): 5679–5689

[58] Holt B F 3rd, Belkhadir Y, Dangl J L. Antagonistic control of disease resistance protein stability in the plant immune system. Science, 2005, 309(5736): 929–932

[59] Botër M, Amigues B, Peart J, Breuer C, Kadota Y, Casais C, Moore G, Kleanthous C, Ochsenbein F, Shirasu K, Guerois R. Structural and functional analysis of SGT1 reveals that its interaction with HSP90 is required for the accumulation of Rx, an R protein involved in plant immunity. Plant Cell, 2007, 19(11): 3791–3804

[60] Bieri S, Mauch S, Shen Q H, Peart J, Devoto A, Casais C, Ceron F, Schulze S, Steinbiss H H, Shirasu K, Schulze-Lefert P. RAR1 positively controls steady state levels of barley MLA resistance proteins and enables sufficient MLA6 accumulation for effective resistance. Plant Cell, 2004, 16(12): 3480–3495

[61] Mestre P, Baulcombe D C. Elicitor-mediated oligomerization of the tobacco N disease resistance protein. Plant Cell, 2006, 18(2): 491–501

[62] Azevedo C, Sadanandom A, Kitagawa K, Freialdenhoven A, Shirasu K, Schulze-Lefert P. The RAR1 interactor SGT1, an essential component of R gene-triggered disease resistance. Science, 2002, 295(5562): 2073–2076

[63] Li Y, Li S, Bi D, Cheng Y T, Li X, Zhang Y. SRFR1 negatively regulates plant NB-LRR resistance protein accumulation to prevent autoimmunity. PLOS Pathogens, 2010, 6(9): e1001111

[64] Kitagawa K, Skowyra D, Elledge S J, Harper J W, Hieter P. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Molecular Cell, 1999, 4(1): 21–33

[65] Zhang M, Botër M, Li K, Kadota Y, Panaretou B, Prodromou C, Shirasu K, Pearl L H. Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes. EMBO Journal, 2008, 27(20): 2789–2798

[66] Catlett M G, Kaplan K B. Sgt1p is a unique co-chaperone that acts as a client adaptor to link Hsp90 to Skp1p. Journal of Biological Chemistry, 2006, 281(44): 33739–33748

[67] Huang S, Monaghan J, Zhong X, Lin L, Sun T, Dong O X, Li X. HSP90s are required for NLR immune receptor accumulation in Arabidopsis. Plant Journal, 2014, 79(3): 427–439

[68] de la Fuente van Bentem S, Vossen J H, de Vries K J, van Wees S, Tameling W I, Dekker H L, de Koster C G, Haring M A, Takken F L, Cornelissen B J. Heat shock protein 90 and its co-chaperone protein phosphatase 5 interact with distinct regions of the tomato I-2 disease resistance protein. Plant Journal, 2005, 43(2): 284–298

[69] Bi D, Johnson K C, Zhu Z, Huang Y, Chen F, Zhang Y, Li X. Mutations in an Atypical TIR-NB-LRR-LIM resistance protein confer autoimmunity. Frontiers of Plant Science, 2011, 2: e71

[70] Liu J, Yang H, Bao F, Ao K, Zhang X, Zhang Y, Yang S. IBR5 Modulates temperature-dependent, R protein CHS3-mediated defense responses in Arabidopsis. PLOS Genetics, 2015, 11(10): e1005584

[71] Yang H, Shi Y, Liu J, Guo L, Zhang X, Yang S. A mutant CHS3 protein with TIR-NB-LRR-LIM domains modulates growth, cell death and freezing tolerance in a temperature-dependent manner in Arabidopsis. Plant Journal, 2010, 63(2): 283–296

[72] Lee J, Nam J, Park H C, Na G, Miura K, Jin J B, Yoo C Y, Baek D, Kim D H, Jeong J C, Kim D, Lee S Y, Salt D E, Mengiste T, Gong Q, Ma S, Bohnert H J, Kwak S S, Bressan R A, Hasegawa P M, Yun D J. Salicylic acid-mediated innate immunity in Arabidopsis is regulated by SIZ1 SUMO E3 ligase. Plant Journal, 2007, 49(1): 79–90

[73] Gou M, Huang Q, Qian W, Zhang Z, Jia Z, Hua J. Sumoylation E3 ligase SIZ1 modulates plant immunity partly through the immune receptor gene SNC1 in Arabidopsis. Molecular Plant-Microbe Interactions, 2017, 30(4): 334–342

[74] Kim S H, Gao F, Bhattacharjee S, Adiasor J A, Nam J C, Gassmann W. The Arabidopsis resistance-like gene SNC1 is activated by mutations in SRFR1 and contributes to resistance to the bacterial effector AvrRps4. PLOS Pathogens, 2010, 6(11): e1001172

[75] Johnson K C M, Zhao J, Wu Z, Roth C, Lipka V, Wiermer M, Li X. The putative kinase substrate MUSE7 negatively impacts the accumulation of NLR proteins. Plant Journal, 2017, 89(6): 1174–1183

[76] Wang R, Ning Y, Shi X, He F, Zhang C, Fan J, Jiang N, Zhang Y, Zhang T, Hu Y, Bellizzi M, Wang G L. Immunity to rice blast disease by suppression of effector-triggered necrosis. Current Biology, 2016, 26(18): 2399–2411

[77] Ning Y, Wang R, Shi X, Zhou X, Wang G L. A layered defense strategy mediated by rice E3 ubiquitin ligases against diverse pathogens. Molecular Plant, 2016, 9(8): 1096–1098

Acknowledgements

We thank Dr. Xin Li, Dr. Guo-Liang Wang and the anonymous reviewers for the constructive suggestions for improving the manuscript, Dr. Lifang Zhao for reviewing an earlier draft. This work was supported by funds from the National Basic Research Program of China (2016YFD0100602), the National Natural Science Foundation of China (31530061) and the Ministry of Agriculture of China (2016ZX08009003-001).

Compliance with ethics guidelinesƒTao Wang, Jiaxin Li, and Qian-Hua Shen declare that they have no conflicts of interest or financial conflicts to disclose.‚‚‚This article is a review and does not contain any studies with human or animal subjects performed by any of the authors.

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