TRIM14 Promotes Noncanonical NF-κB Activation by Modulating P100/p52 Stability Via Selective Autophagy

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2020 Jan 11

PMID 31921549

Citations 26

Authors

Meixin Chen

Zhiyao Zhao

Qingcai Meng

Puping Liang

Zexiong Su

Yaoxing Wu

Junjiu Huang

Jun Cui

Affiliations

Soon will be listed here.

Abstract

The noncanonical NF-κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-κB signaling largely relies on the abundance as well as the processing of the NF-κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-κB signaling pathway. TRIM14 promotes noncanonical NF-κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-κB-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-κB signaling and highlight the crosstalk between autophagy and innate immunity.

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References

Korolchuk V, Menzies F, Rubinsztein D . A novel link between autophagy and the ubiquitin-proteasome system. Autophagy. 2009; 5(6):862-3. DOI: 10.4161/auto.8840. View

Liu K, Zhang L, Zhao Q, Zhao Z, Zhi F, Qin Y . SKP2 attenuates NF-κB signaling by mediating IKKβ degradation through autophagy. J Mol Cell Biol. 2018; 10(3):205-215. DOI: 10.1093/jmcb/mjy012. View

Jin S, Tian S, Chen Y, Zhang C, Xie W, Xia X . USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. EMBO J. 2016; 35(8):866-80. PMC: 4972138. DOI: 10.15252/embj.201593596. View

Munz C . Selective macroautophagy for immunity. Immunity. 2010; 32(3):298-9. DOI: 10.1016/j.immuni.2010.03.002. View

Grivennikov S, Karin E, Terzic J, Mucida D, Yu G, Vallabhapurapu S . IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009; 15(2):103-13. PMC: 2667107. DOI: 10.1016/j.ccr.2009.01.001. View

Camacho-Barquero L, Villegas I, Sanchez-Calvo J, Talero E, Sanchez-Fidalgo S, Motilva V . Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol. 2007; 7(3):333-42. DOI: 10.1016/j.intimp.2006.11.006. View

Du Y, Duan T, Feng Y, Liu Q, Lin M, Cui J . LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I for autophagic degradation. EMBO J. 2017; 37(3):351-366. PMC: 5793803. DOI: 10.15252/embj.201796781. View

Tan P, He L, Cui J, Qian C, Cao X, Lin M . Assembly of the WHIP-TRIM14-PPP6C Mitochondrial Complex Promotes RIG-I-Mediated Antiviral Signaling. Mol Cell. 2017; 68(2):293-307.e5. DOI: 10.1016/j.molcel.2017.09.035. View

Arabi A, Ullah K, Branca R, Johansson J, Bandarra D, Haneklaus M . Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway. Nat Commun. 2012; 3:976. PMC: 4354031. DOI: 10.1038/ncomms1975. View

10.

Nenasheva V, Stepanenko E, Makarova I, Khaidarova N, Antonov S, Kozikova L . Expression of the human TRIM14 and its mutant form (P207L) promotes apoptosis in transgenic loaches. Mol Biol Rep. 2018; 45(6):2087-2093. DOI: 10.1007/s11033-018-4365-7. View

11.

Sheng L, Zhou Y, Chen Z, Ren D, Cho K, Jiang L . NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nat Med. 2012; 18(6):943-9. PMC: 3766969. DOI: 10.1038/nm.2756. View

12.

Jin J, Hu H, Li H, Yu J, Xiao Y, Brittain G . Noncanonical NF-κB pathway controls the production of type I interferons in antiviral innate immunity. Immunity. 2014; 40(3):342-54. PMC: 3983709. DOI: 10.1016/j.immuni.2014.02.006. View

13.

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

14.

Isogai S, Morimoto D, Arita K, Unzai S, Tenno T, Hasegawa J . Crystal structure of the ubiquitin-associated (UBA) domain of p62 and its interaction with ubiquitin. J Biol Chem. 2011; 286(36):31864-74. PMC: 3173063. DOI: 10.1074/jbc.M111.259630. View

15.

Kim J, Morgan M, Kim D, Lee J, Bai L, Lin Y . TNFα induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2. J Cell Sci. 2011; 124(Pt 4):647-56. DOI: 10.1242/jcs.075770. View

16.

Liu J, Qian C, Cao X . Post-Translational Modification Control of Innate Immunity. Immunity. 2016; 45(1):15-30. DOI: 10.1016/j.immuni.2016.06.020. View

17.

Zhou Z, Jia X, Xue Q, Dou Z, Ma Y, Zhao Z . TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I-like receptor-mediated innate immune response. Proc Natl Acad Sci U S A. 2014; 111(2):E245-54. PMC: 3896185. DOI: 10.1073/pnas.1316941111. View

18.

Sun S . Non-canonical NF-κB signaling pathway. Cell Res. 2010; 21(1):71-85. PMC: 3193406. DOI: 10.1038/cr.2010.177. View

19.

Burkitt M, Hanedi A, Duckworth C, Williams J, Tang J, OReilly L . NF-κB1, NF-κB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice. J Pathol. 2015; 236(3):326-36. PMC: 4737252. DOI: 10.1002/path.4527. View

20.

Ding W, Yin X . Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 2007; 4(2):141-50. DOI: 10.4161/auto.5190. View