TRIM27 cooperates with STK38L to inhibit ULK1‐mediated autophagy and promote tumorigenesis

Autophagy represents a fundamental mechanism for maintaining cell survival and tissue homeostasis in response to physiological and pathological stress. Autophagy initiation converges on the FIP200‐ATG13‐ULK1 complex wherein the serine/threonine kinase ULK1 plays a central role. Here, we reveal that the E3 ubiquitin ligase TRIM27 functions as a negative regulatory component of the FIP200‐ATG13‐ULK1 complex. TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48‐linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels. However, during starvation‐induced autophagy, TRIM27 catalyzes non‐degradative K6‐ and K11‐linked ubiquitination of the serine/threonine kinase 38‐like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27‐mediated hyper‐ubiquitination of ULK1. This cooperative mechanism serves to restrain the amplitude and duration of autophagy. Further evidence from mouse models shows that basal autophagy levels are increased in Trim27 knockout mice and that Trim27 differentially regulates tumorigenesis and metastasis. Our study identifies a key role of STK38L‐TRIM27‐ULK1 signaling axis in negatively controlling autophagy with relevance established in human breast cancer.

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