Study Reveals TBK1 as a Negative Regulator of IRGQ-Mediated Autophagy
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In a study published in Nature Communications, a team of SFB 1177 scientists uncovered a previously unknown regulatory mechanism of selective autophagy.
The researchers demonstrate that the autophagy receptor IRGQ functions not only as a cargo receptor, but also as an autophagy initiation hub by bringing together GABARAPL2, LC3B and the autophagy machinery to promote ATG8 lipidation and autophagic flux. The study further proposes that the IRGQ-GABARAPL2 complex acts as a scaffolding platform that nucleates autophagy initiation through dual hATG8 interactions and recruitment of the autophagy-initiation machinery.
In addition, TBK1 was unexpectedly identified as a negative regulator of this pathway. Upon TBK1 activation, GABARAPL2 is phosphorylated at serine 10, resulting in destabilization of the IRGQ-GABARAPL2 complex. This selectively reduces the autophagic flux of GABARAPL2 and IRGQ-associated cargo, including MHC-I, without broadly impairing bulk autophagy.
These findings expand the current understanding of TBK1, which is often viewed as a pro-autophagic kinase. Instead, the study demonstrates that TBK1 can fine-tune selective autophagy in a context-dependent manner by disassembling specific receptor-ATG8 complexes. The work therefore provides new insights into the regulation of autophagy, immune responses and MHC-I quality control, and reveals additional layers of regulation mediated by kinase signaling networks.
