2. Academic Validation
  3. SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

  • Autophagy. 2023 Nov 1:1-17. doi: 10.1080/15548627.2023.2267413.
Qin Xia 1,  Hanfei Zheng 1,  Yang Li 1,  Wanting Xu 1,  Chengwei Wu 1,  Jiachen Xu 2,  Shanhu Li 3,  Lingqiang Zhang 4,  Lei Dong 1
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing, China.
  • 2 State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China.
  • 4 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
PMID: 37909662 DOI: 10.1080/15548627.2023.2267413
Abstract

Macroautophagy/Autophagy is a homeostatic process in response to multiple signaling, such as the lysosome-dependent recycling process of cellular components. Starvation-induced mTOR inactivation and PPP3/calcineurin activation were shown to promote the nuclear translocation of TFEB. However, the mechanisms via which signals from endomembrane damage are transmitted to activate PPP3/calcineurin and orchestrate autophagic responses remain unknown. This study aimed to show that Autophagy regulator SMURF1 controlled TFEB nuclear import for transcriptional activation of the lysosomal biogenesis. We showed that blocking SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation. It revealed galectins recognized endolysosomal damage, and led to recruitment of SMURF1 and the PPP3/calcineurin apparatus on lysosomes. SMURF1 interacts with both LGALS3 and PPP3CB to form the LGALS3-SMURF1-PPP3/calcineurin complex. Importantly, this complex further stabilizes TFEB, thereby activating TFEB for lysosomal biogenesis. We determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of mTORC1 inhibition. In addition, SMURF1 is required for PPP3/calcineurin activity as a positive regulator of TFEB. SMURF1 controlled the Phosphatase activity of the PPP3CB by promoting the dissociation of its autoinhibitory domain (AID) from its catalytic domain (CD). Overexpression of SMURF1 showed similar effects as the constitutive activation of PPP3CB. Thus, SMURF1, which bridges environmental stress with the core autophagosomal and autolysosomal machinery, interacted with endomembrane sensor LGALS3 and Phosphatase PPP3CB to control TFEB activation.Abbreviations: ATG: autophagy-related; LLOMe: L-Leucyl-L-Leucine methyl ester; ML-SA1: mucolipin synthetic agonist 1; MTOR: mechanistic target of rapamycin kinase; PPP3CB: protein Phosphatase 3 catalytic subunit beta; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; TFEB: transcription factor EB.

Keywords

Autophagy; PPP3/Calcineurin; SMURF1; TFEB; lysosomal biogenesis.

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