MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy
Open accessAbstract
NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation. Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. Consequently, NRBF2 in its unphosphorylated form promotes PtdIns3K lipid kinase activity and autophagy flux, whereas its phosphorylated form blocks them. This study reveals NRBF2 as a critical molecular switch of PtdIns3K and autophagy activation, and its on/off state is precisely controlled by MTORC1 through phosphorylation.
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NRBF2 has been demonstrated to positively regulate autophagy.
“NRBF2 has been demonstrated to positively regulate autophagy.25,28,30”
From NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models (2017) · cites this paper as [30]
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References 46 · Cited by 92
- Authors
- Ma, X., Zhang, S., He, L., Rong, Y., Brier, L. W., Sun, Q., Liu, R., Fan, W., Chen, S., Yue, Z., Kim, J., Guan, K.-L., Li, D., & Zhong, Q.
- Affiliations
- State Key Laboratory of Animal Nutrition (CN)
- The University of Texas Southwestern Medical Center (US)
- University of California, Berkeley (US)
- National Institute of Biological Sciences, Beijing (CN)
- Icahn School of Medicine at Mount Sinai (US)
- University of California San Diego (US)
- Corresponding author
- Ma, Xi
- Zhong, Qing
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2017-01-31
- Volume
- 13
- Issue
- 3
- Pages
- 592-607
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC5361594
- OpenAlex
- W2567875529
- Cited by
- 92
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 28 · 2020: 7 · 2019: 11 · 2018: 10 · 2017: 3
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP140320, RP170382)
- National Natural Science Foundation of China (31528018, B16044, 31472101)
- China Scholarship Council (B16044)
- Higher Education Discipline Innovation Project (B16044.)
- National Institutes of Health (GM116908)
- Beijing Nova Program (xx2013055)
- National Key Research and Development Program of China (2013CB117301, B16044)
- National Cancer Institute (R35CA196878)
- National Institute of General Medical Sciences (R01GM051586, R01GM116908)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- mTORC1, protein phosphorylation, ULK1 complex, nutrient deprivation, autophagic flux, lipid kinase activity
- MeSH terms
- Autophagy-Related Proteins, Autophagy-Related Protein-1 Homolog, Mechanistic Target of Rapamycin Complex 1, Amino Acid Sequence, Animals, Autophagy, Phosphorylation, Phosphoserine, Protein Binding, Stress, Physiological, Substrate Specificity, Transcription Factors, Trans-Activators, Mice, Class III Phosphatidylinositol 3-Kinases
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