+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity



Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity



Cell 141(2): 315-330



RIG-I detects invading viral RNA and activates the transcription factors NF-kappaB and IRF3 through the mitochondrial protein MAVS. Here we show that RNA bearing 5'-triphosphate strongly activates the RIG-I-IRF3 signaling cascade in a reconstituted system composed of RIG-I, mitochondria, and cytosol. Activation of RIG-I requires not only RNA but also polyubiquitin chains linked through lysine 63 (K63) of ubiquitin. RIG-I binds specifically to K63-polyubiquitin chains through its tandem CARD domains in a manner that depends on RNA and ATP. Mutations in the CARD domains that abrogate ubiquitin binding also impair RIG-I activation. Remarkably, unanchored K63-ubiquitin chains, which are not conjugated to any target protein, potently activate RIG-I. These ubiquitin chains function as an endogenous ligand of RIG-I in human cells. Our results delineate the mechanism of RIG-I activation, identify CARD domains as a ubiquitin sensor, and demonstrate that unanchored K63-polyubiquitin chains are signaling molecules in antiviral innate immunity.

(PDF emailed within 0-6 h: $19.90)

Accession: 055411125

Download citation: RISBibTeXText

PMID: 20403326

DOI: 10.1016/j.cell.2010.03.029


Related references

Method for the Purification of Endogenous Unanchored Polyubiquitin Chains. Methods in Molecular Biology 1449: 203-213, 2018

Purification of Unanchored Polyubiquitin Chains from Influenza Virions. Methods in Molecular Biology 1836: 329-342, 2018

Insights into the molecular composition of endogenous unanchored polyubiquitin chains. Journal of Proteome Research 11(3): 1969-1980, 2012

Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Science Advances 5(5): Eaau8857, 2019

Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clinical Immunology 189: 4-13, 2016

Functions of Linear Ubiquitin Chains in the NF-κB Pathway : Linear Polyubiquitin in NF-κB Signaling. Sub-Cellular Biochemistry 54: 100-106, 2016

Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses. Plos Pathogens 9(6): E1003416, 2014

Signaling pathway of autophagy associated with innate immunity. Autophagy 4(1): 110-112, 2007

Genetic analysis reveals functions of atypical polyubiquitin chains. Elife 7, 2018

Innate immunity induced by fungal β-glucans via dectin-1 signaling pathway. International Journal of Medicinal Mushrooms 16(1): 1-16, 2015

Involvement of the Toll-like receptor 9 signaling pathway in the induction of innate immunity by baculovirus. Journal of Virology 79(5): 2847-2858, 2005

Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer. Cell Reports 25(13): 3721-3732.E6, 2018

NF-kappaB signaling: flipping the switch with polyubiquitin chains. Current Biology 14(20): R898-R900, 2004

Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. Journal of Biological Chemistry 284(8): 5030-5041, 2009

MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway. Elife 8, 2019