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 ...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 CARDRIG-I-CARDMAVS 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.展开更多
基金supported by grants from the National Natural Science Foundation of China(31730026,81930039,32000633)National Key Research and Development Program(2021YFC2300603),Natural Science Foundation of Shandong Province(ZR2020QH136)China Postdoctoral Science Foundation(2020M682187),and Postdoctoral Innovation Project of Shandong Province(202002012).
文摘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 CARDRIG-I-CARDMAVS 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.
