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TitleOrdered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.
Journal, issue, pagesImmunity, Vol. 54, Issue 10, Page 2218-22230.e5, Year 2021
Publish dateOct 12, 2021
AuthorsBin Song / Yun Chen / Xin Liu / Fei Yuan / Eddie Yong Jun Tan / Yixuan Lei / Ning Song / Yinqi Han / Bruce D Pascal / Patrick R Griffin / Cheng Luo / Bin Wu / Dahai Luo / Jie Zheng /
PubMed AbstractThe RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we ...The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUb (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (CARDs). Cryoelectron microscopy structures of a polyUb-bound CARDs tetramer and a polyUb-bound CARDs-CARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging CARDs and CARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.
External linksImmunity / PubMed:34644557
MethodsEM (single particle)
Resolution3.2 - 3.3 Å
Structure data

30784

7dni

EMDB-30784, PDB-7dni:
MDA5 CARDs-MAVS CARD polyUb complex
Method: EM (single particle) / Resolution: 3.2 Å

30785

7dnj

EMDB-30785, PDB-7dnj:
K63-polyUb MDA5CARDs complex
Method: EM (single particle) / Resolution: 3.3 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / Signaling / polyubiquitin / signaling complex

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