Park H, Heo H, Song Y, Lee MS, Cho Y, Lee JS, Chang J, Lee S

Tripartite motif (TRIM) family proteins are increasingly recognized as important regulators of autophagy under various physiological and pathological conditions. TRIM22 has been previously shown to mediate autophagosome-lysosome fusion, but its potential role in earlier stages of autophagy remained unexplored. In this study, we investigated the function of TRIM22 in autophagy ...

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initiation. Overexpression of TRIM22 increased LC3-II levels and enhanced autophagic flux without affecting mTOR and AMPK activity. We found that TRIM22 interacts with components of both the ULK1 complex and the class III PI3K complex through distinct domains, recruiting them into punctate structures that represent autophagosome formation sites. Domain mapping revealed that the SPRY domain mediates interactions with ATG13 and FIP200, while the N-terminal region interacts with ULK1 and ATG101. The B-box domain of TRIM22 was identified as crucial for its interaction with Beclin-1, a key component of the class III PI3K complex. Deletion of this domain impaired the ability of TRIM22 to assemble the class III PI3K complex and induce autophagic flux. Interestingly, competitive binding assays revealed that Beclin-1 and PLEKHM1 bind to the same region of TRIM22, suggesting a mechanism for coordinating different stages of autophagy. The Alzheimer's disease-associated TRIM22 variant R321K maintained autophagy initiation function in both cell lines and primary neurons. These findings demonstrate that TRIM22 acts as a scaffold protein to promote autophagy initiation, in addition to its previously described role in autophagosome-lysosome fusion. Our study provides new insights into the molecular mechanisms by which TRIM proteins regulate multiple stages of the autophagy process.

Date: May. 08, 2025

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