4.7 Article

MAVS-loaded unanchored Lys63-linked polyubiquitin chains activate the RIG-I-MAVS signaling cascade

Journal

CELLULAR & MOLECULAR IMMUNOLOGY
Volume -, Issue -, Pages -

Publisher

CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-023-01065-2

Keywords

MAVS; Aggregation; Unanchored K63-linked polyubiquitin chains; RIG-I; USP10

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In this study, the researchers discovered that K63-linked polyubiquitin chains loaded on MAVS can be recognized by RIG-I to initiate MAVS aggregation. They also identified Ube2N as a major enzyme involved in the polyubiquitination of MAVS and found that it cooperates with Riplet and TRIM31 to promote unanchored polyubiquitination. Additionally, they identified USP10 as a deubiquitinating enzyme that removes unanchored polyubiquitin chains from MAVS.
The adaptor molecule MAVS forms prion-like aggregates to govern the RIG-I-like receptor (RLR) signaling cascade. Lys63 (K63)-linked polyubiquitination is critical for MAVS aggregation, yet the underlying mechanism and the corresponding E3 ligases and deubiquitinating enzymes (DUBs) remain elusive. Here, we found that the K63-linked polyubiquitin chains loaded on MAVS can be directly recognized by RIG-I to initiate RIG-I-mediated MAVS aggregation with the prerequisite of the CARD(RIG-I)-CARD(MAVS) interaction. Interestingly, many K63-linked polyubiquitin chains attach to MAVS via an unanchored linkage. We identified Ube2N as a major ubiquitin-conjugating enzyme for MAVS and revealed that Ube2N cooperates with the E3 ligase Riplet and TRIM31 to promote the unanchored K63-linked polyubiquitination of MAVS. In addition, we identified USP10 as a direct DUB that removes unanchored K63-linked polyubiquitin chains from MAVS. Consistently, USP10 attenuates RIG-I-mediated MAVS aggregation and the production of type I interferon. Mice with a deficiency in USP10 show more potent resistance to RNA virus infection. Our work proposes a previously unknown mechanism for the activation of the RLR signaling cascade triggered by MAVS-attached unanchored K63-linked polyubiquitin chains and establishes the DUB USP10 and the E2:E3 pair Ube2N-Riplet/TRIM31 as a specific regulatory system for the unanchored K63-linked ubiquitination and aggregation of MAVS upon viral infection.

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