Phosphorylation of OTUB1 promotes autophagy initiation under starvation
What this study shows
Under starvation, ERK phosphorylates the deubiquitinase OTUB1 at S118, which stabilizes it by letting it out-compete TRIM29 for binding to ANXA2. Stabilized OTUB1 upregulates DEPTOR, a natural mTOR inhibitor, which suppresses mTOR and triggers autophagy. In mice, restoring this fasting-triggered ERK-OTUB1-DEPTOR-mTOR axis countered the mTOR-activating effect of a Western diet and eased MASLD (fatty liver disease) progression, giving a mechanistic account of how fasting benefits the liver.
Abstract
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Eukaryotes initiate autophagy in response to environmental challenges such as nutrient deprivation. However, the mechanisms governing autophagy initiation remain incompletely understood. Here, we demonstrated that OTUB1 phosphorylation plays a key role in starvation-induced autophagy initiation. Specifically, ERK phosphorylates OTUB1 at S118 during starvation. This phosphorylation enables competitive binding of ANXA2 to OTUB1, disrupting its interaction with TRIM29 and enhancing OTUB1 stability. Stabilized OTUB1 upregulated DEPTOR, thereby inhibiting mTOR and inducing autophagy.
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse (Western diet / MASLD model); cultured cells (starvation)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse (Western diet / MASLD model); cultured cells (starvation) |
| Journal | Nature Communications |
| Year | 2026 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41467-026-76796-7 · PMID 42736303 · Free full text (PMC13574767) |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
People in the Atlas
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Researcher studying phosphorylation-based control of autophagy initiation and its role in metabolic liver disease
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Biochemist studying deubiquitinase signalling in autophagy and metabolic disease
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | Starvation/fasting; OTUB1 S118 phosphomutants; Western diet in mice |
| Target | ERK-OTUB1-DEPTOR-mTOR-autophagy axis |
| Model | Cultured cells; mouse (Western diet MASLD model) |
| Effect | ERK-phosphorylated OTUB1 stabilises DEPTOR, inhibiting mTOR and initiating autophagy; restoring the axis eased MASLD in mice. |
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