Optineurin Provides a Mitophagy Contact Site for TBK1 Activation
EMBO journal(2024)
摘要
Tank-binding kinase 1 (TBK1) is a Ser/Thr kinase that is involved in many intracellular processes, such as innate immunity, cell cycle, and apoptosis. TBK1 is also important for phosphorylating the autophagy adaptors that mediate the selective autophagic removal of damaged mitochondria. However, the mechanism by which PINK1-Parkin-mediated mitophagy activates TBK1 remains largely unknown. Here, we show that the autophagy adaptor optineurin (OPTN) provides a unique platform for TBK1 activation. Both the OPTN-ubiquitin and the OPTN-pre-autophagosomal structure (PAS) interaction axes facilitate assembly of the OPTN-TBK1 complex at a contact sites between damaged mitochondria and the autophagosome formation sites. At this assembly point, a positive feedback loop for TBK1 activation is initiated that accelerates hetero-autophosphorylation of the protein. Expression of monobodies engineered here to bind OPTN impaired OPTN accumulation at contact sites, as well as the subsequent activation of TBK1, thereby inhibiting mitochondrial degradation. Taken together, these data show that a positive and reciprocal relationship between OPTN and TBK1 initiates autophagosome biogenesis on damaged mitochondria. Tank-binding kinase 1 (TBK1), a Ser/Thr kinase involved in many intracellular processes, is important for the selective autophagic removal of damaged mitochondria. This work addresses the mechanism by which TBK1 becomes activated in this context.The autophagy adaptor optineurin (OPTN) provides a platform for TBK1 activation via autophosphorylation as damaged mitochondria are removed. OPTN accumulates at contact sites between a damaged mitochondrion and the pre-autophagosomal structure (PAS). Not only the interaction between OPTN and ubiquitin but also the interaction between OPTN and the PAS facilitates TBK1 activation. OPTN-TBK1 assembly at the contact site drives a positive feedback loop for TBK1 activation. Monobodies against OPTN physically block OPTN assembly at the contact site and impair the elimination of damaged mitochondria. Tank-binding kinase 1 localizes to clusters of optineurin on the surface of damaged mitochondria, where its autophosphorylation promotes growth of the pre-autophagosomal structure.
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关键词
Autophagy,Mitochondria,Parkin,PINK1,Ubiquitin
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