LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation

Abstract

The innate immune systemis critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, wefound that LRRK2, encoded by a gene implicated in Crohn’s disease, leprosy and familial Parkinson’s disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide (MDP), Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon Nod2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.

Keywords

LRRK2 / Nod2 / Rip2 / NF-κB activation / Inflammation

References

[1] Bertrand MJ, Doiron K, Labbe K, Korneluk RG, Barker PA, Saleh M (2009) Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30:789–801

[2] Caruso R, Warner N, Inohara N, Nunez G (2014) NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41:898–908

[3] Damgaard RB, Nachbur U, Yabal M (2012) The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell 46:746–758

[4] Dorsch M, Wang A, Cheng H (2006) Identification of a regulatory autophosphorylation site in the serine-threonine kinase RIP2. Cell Signal 18:2223–2229

[5] Franke A, McGovern DP, Barrett JC (2010) Genome-wide metaanalysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125

[6] Gardet A, Benita Y, Li C (2010) LRRK2 is involved in the IFNgamma response and host response to pathogens. J Immunol 185:5577–5585

[7] Gillardon F (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability–a point of convergence in Parkinsonian neurodegeneration? J Neurochem 110:1514–1522

[8] Hitotsumatsu O, Ahmad RC, Tavares R (2008) The ubiquitinediting enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 28:381–390

[9] Hsu CH, Chan D, Greggio E (2010) MKK6 binds and regulates expression of Parkinson’s disease-related protein LRRK2. J Neurochem 112:1593–1604

[10] Imai Y, Gehrke S, Wang HQ (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. Embo J 27:2432–2443

[11] Ito G, Katsemonova K, Tonelli F (2016) Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. Biochem J 473:2671–2685

[12] Jaleel M, Nichols RJ, Deak M (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem J 405:307–317

[13] Jostins L, Ripke S, Weersma RK (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124

[14] Keestra-Gounder AM, Byndloss MX, Seyffert N (2016) NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532(7599):394–397

[15] Kobayashi K, Inohara N, Hernandez LD (2002) RICK/Rip2/ CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416:194–199

[16] Kubo M, Nagashima R, Ohta E (2016) Leucine-rich repeat kinase 2 is a regulator of B cell function, affecting homeostasis, BCR signaling, IgA production, and TI antigen responses. J Neuroimmunol 292:1–8

[17] Leszek J, Barreto GE, Gasiorowski K, Koutsouraki E, Avila-Rodrigues M, Aliev G (2016) Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS Neurol Disord Drug Targets 15:329–336

[18] Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12:1063–1070

[19] Lytton J, Westlin M, Hanley MR (1991) Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem 266:17067–17071

[20] Magalhaes JG, Lee J, Geddes K, Rubino S, Philpott DJ, Girardin SE (2011) Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur J Immunol 41:1445–1455

[21] McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291

[22] Nakamura N, Lill JR, Phung Q (2014) Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509:240–244

[23] Paisan-Ruiz C, Jain S, Evans EW (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600

[24] Park JH, Kim YG, McDonald C (2007) RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178:2380–2386

[25] Peterson LW, Artis D (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14:141–153

[26] Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE (2014) NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol 14:9–23

[27] Rioux JD, Xavier RJ, Taylor KD (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39:596–604

[28] Rocha NP, de Miranda AS, Teixeira AL (2015) Insights into neuroinflammation in Parkinson’s disease: from biomarkers to anti-inflammatory based therapies. Biomed Res Int 2015:628192

[29] Stafa K, Trancikova A, Webber PJ, Glauser L, West AB, Moore DJ (2012) GTPase activity and neuronal toxicity of Parkinson’s disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 8:e1002526

[30] Suzuki K, Akama T, Kawashima A, Yoshihara A, Yotsu RR, Ishii N (2012) Current status of leprosy: epidemiology, basic science and clinical perspectives. J Dermatol 39:121–129

[31] Wandu WS, Tan C, Ogbeifun O (2015) Leucine-rich repeat kinase 2 (Lrrk2) deficiency diminishes the development of experimental autoimmune uveitis (EAU) and the adaptive immune response. PLoS One 10:e0128906

[32] Yang Y, Yin C, Pandey A, Abbott D, Sassetti C, Kelliher MA (2007) NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J Biol Chem 282:36223–36229

[33] Zhang FR, Huang W, Chen SM (2009) Genomewide association study of leprosy. N Engl J Med 361:2609–2618

[34] Zhang Q, Pan Y, Yan R (2015) Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat Immunol 6 (9):918–926

[35] Zhu Y, Wang C, Yu M, Cui J, Liu L, Xu Z (2013) ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein Cell 4:711–721

[36] Zimprich A, Biskup S, Leitner P (2004) Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44:601–607

RIGHTS & PERMISSIONS

2016 The Author(s) 2016. This article is published with open access at Springerlink.com and journal.hep.com.cn