bims-lymeca 2023-11-05 papers

Issue of 2023‒11‒05
four papers selected by
Harilaos Filippakis, University of New England

Autophagy. 2023 Nov 01. 1-17

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

Qin Xia, Hanfei Zheng, Yang Li, Wanting Xu, Chengwei Wu, Jiachen Xu, Shanhu Li, Lingqiang Zhang, Lei Dong.

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

DOI: https://doi.org/10.1080/15548627.2023.2267413

J Cell Sci. 2023 Nov 03. pii: jcs.261402. [Epub ahead of print]

Cholesterol regulates insulin-induced mTORC1 signaling.

Kolaparamba V Navyasree, Shikha T Ramesh, Perunthottathu K Umasankar.

The rapid activation of the critical kinase, mechanistic target of rapamycin complex-1 (mTORC1) by insulin is key to cell growth in mammals, but the regulatory factors remain unclear. Here, we demonstrate that cholesterol plays a crucial role in the regulation of insulin-stimulated mTORC1 signaling. The rapid progression of insulin-induced mTORC1 signaling declines in sterol-depleted cells and restores in cholesterol-repleted cells. In insulin-stimulated cells, cholesterol promotes recruitment of mTORC1 onto lysosomes without affecting insulin-induced dissociation of the TSC complex from lysosomes, thereby enabling complete activation of mTORC1. We also show that under prolonged starvation conditions, cholesterol coordinates with autophagy to support mTORC1 reactivation on lysosomes thereby restoring insulin-responsive mTORC1 signaling. Further, we identify that Smith-Lemli-Opitz Syndrome (SLOS) patient fibroblasts and HeLa-SLOS model which are deficient in cholesterol biosynthesis exhibit defects in insulin-mTORC1 growth axis. These defects are rescued by supplementation of exogenous cholesterol or by expression of constitutively active Rag GTPase, a downstream activator of mTORC1. Overall, our findings propose novel signal integration mechanisms to achieve spatial and temporal control of mTORC1-dependent growth signaling and their aberrations in disease.

Keywords: Cholesterol; Insulin; Lysosome; Signaling; mTORC1

DOI: https://doi.org/10.1242/jcs.261402

FEBS J. 2023 Nov 03.

Autophagy of the ER: the secretome finds the lysosome.

Jeffrey Knupp, Madison L Pletan, Peter Arvan, Billy Tsai.

Lysosomal degradation of the endoplasmic reticulum (ER) and its components through the autophagy pathway has emerged as a major regulator of ER proteostasis. Commonly referred to as ER-phagy and ER-to-lysosome-associated degradation (ERLAD), how the ER is targeted to the lysosome has been recently clarified by a growing number of studies. Here, we summarize the discoveries of the molecular components required for lysosomal degradation of the ER and their proposed mechanisms of action. Additionally, we discuss how cells employ these machineries to create the different routes of ER-lysosome-associated degradation. Further, we review the role of ER-phagy in viral infection pathways, as well as the implication of ER-phagy in human disease. In sum, we provide a comprehensive overview of the current field of ER-phagy.

Keywords: ER-phagy; autophagy; endoplasmic reticulum; protein quality control; virus-host interactions

DOI: https://doi.org/10.1111/febs.16986

J Cell Biol. 2023 Dec 04. pii: e202305032. [Epub ahead of print]222(12):

Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.

Eric D Leisten, Abby C Woods, Yvette C Wong.

Live super-resolution microscopy has allowed for new insights into recently identified mitochondria-lysosome contact sites, which mediate crosstalk between mitochondria and lysosomes, including co-regulation of Rab7 GTP hydrolysis and Drp1 GTP hydrolysis. Here, we highlight recent findings and future perspectives on this dynamic pathway and its roles in health and disease.

DOI: https://doi.org/10.1083/jcb.202305032