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A Conserved Myotubularin-Related Phosphatase Regulates Autophagy by Maintaining Autophagic Flux

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A Conserved Myotubularin-Related Phosphatase Regulates Autophagy by Maintaining Autophagic Flux University of Massachusetts Medical School eScholarship@UMMS Open Access Publications by UMMS Authors 2020-11-02 A conserved myotubularin-related phosphatase regulates autophagy by maintaining autophagic flux Elizabeth A. Allen University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Cell Biology Commons, Cellular and Molecular Physiology Commons, Developmental Biology Commons, and the Enzymes and Coenzymes Commons Repository Citation Allen EA, Amato C, Fortier TM, Velentzas PD, Wood W, Baehrecke EH. (2020). A conserved myotubularin- related phosphatase regulates autophagy by maintaining autophagic flux. Open Access Publications by UMMS Authors. https://doi.org/10.1083/jcb.201909073. Retrieved from https://escholarship.umassmed.edu/oapubs/4464 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Publications by UMMS Authors by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. ARTICLE A conserved myotubularin-related phosphatase regulates autophagy by maintaining autophagic flux Elizabeth A. Allen1, Clelia Amato2, Tina M. Fortier1, Panagiotis Velentzas1,WillWood2, and Eric H. Baehrecke1 Macroautophagy (autophagy) targets cytoplasmic cargoes to the lysosome for degradation. Like all vesicle trafficking, Downloaded from http://rupress.org/jcb/article-pdf/219/11/e201909073/1049533/jcb_201909073.pdf by Massachusetts Worcester user on 10 January 2021 autophagy relies on phosphoinositide identity, concentration, and localization to execute multiple steps in this catabolic process. Here, we screen for phosphoinositide phosphatases that influence autophagy in Drosophila and identify CG3530. CG3530 is homologous to the human MTMR6 subfamily of myotubularin-related 3-phosphatases, and therefore, we named it dMtmr6. dMtmr6, which is required for development and viability in Drosophila, functions as a regulator of autophagic flux in multiple Drosophila cell types. The MTMR6 family member MTMR8 has a similar function in autophagy of higher animal cells. Decreased dMtmr6 and MTMR8 function results in autophagic vesicle accumulation and influences endolysosomal homeostasis. Introduction Cells rely on macroautophagy (hereafter autophagy) to deliver autophagosomal SNARE protein Syntaxin 17 (Takatsetal.,2013´ ; sequestered cytoplasmic cargoes to lysosomes for degradation. Itakura et al., 2012). When lysosomal enzymes complete auto- Basal autophagy levels maintain cellular homeostasis, and acti- phagic cargo degradation, then autolysosome reformation con- vated autophagy mitigates several cellular stresses, including tributes to regeneration of the lysosomal pool, which further nutrient deprivation. Autophagy begins with the formation of promotes homeostasis (Yu et al., 2010). Both excessive and in- an isolation membrane that elongates and encloses cargoes to sufficient autophagy can promote disease by dysregulating au- eventually form a closed double-membrane autophagosome that tophagic flux, a term that describes the quantity of autophagic fuses with lysosomes to become an autolysosome (Yu et al., degradation (Dowling et al., 2015; Levine and Kroemer, 2019; 2018). Lysosomal enzymes, including cathepsins, break down Yoshii and Mizushima, 2017), making rate control a key com- autophagic cargoes into macromolecules, which are later ef- ponent to each step of autophagy. fluxed into the cytoplasm for use in anabolic cellular processes. Vesicular membrane identity and trafficking rely largely Pioneering yeast experiments defined the core autophagic mo- upon PI identity, concentration, and coincidence (Schink et al., lecular mechanisms (Tsukada and Ohsumi, 1993). However, 2016). PI kinases (PIKs) and phosphatases can switch the 3-, 4-, metazoans such as Drosophila melanogaster possess an enhanced and 5-hydroxyl group phosphates of the inositol ring to generate repertoire of autophagic machinery beyond those required in seven distinct cellular PIs. Membrane-embedded PIs recruit yeast, thus providing a multicellular in vivo experimental sys- effectors to control membrane dynamics via multiple mecha- tem to study autophagy (Mulakkal et al., 2014; Zhang and nisms, including membrane fusion, scission, and shaping. In the Baehrecke, 2015). endolysosomal system, PI(3)P is the major PI species on endo- From initiation to completion, autophagy is regulated by >30 somes following PI conversion from PI(4,5)P2, which is required conserved core autophagy-related (Atg/ATG) proteins (Galluzzi for endocytosis (Wallroth and Haucke, 2018). Recycling endo- et al., 2017). Autophagy initiation and autophagosome biogenesis somes rely on a PI(3)P loss (Campa et al., 2018) and PI(4)P gain require the Atg1–ULK1 serine–threonine kinase complex, the (Ketel et al., 2016), while degradative PI(3)P-positive endosomes vacuolar protein sorting (Vps34) class III phosphoinositide (PI) require PI(3,5)P2 production by the PI(3)P 5-kinase PIKFYVE for 3-kinase (PI3K) complex, and the Atg8 conjugation system. endosomal sorting complexes required for transport (ESCRT)-III Autophagosome–lysosome fusion utilizes dozens of proteins, recruitment and delivery to multivesicular bodies (Kim et al., including many shared with the endocytic pathway and the 2014; Hasegawa et al., 2017). Similar PI conversion events occur ............................................................................................................................................................................. 1Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA; 2Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK. Correspondence to Eric H. Baehrecke: [email protected]. © 2020 Allen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Rockefeller University Press https://doi.org/10.1083/jcb.201909073 1of18 J. Cell Biol. 2020 Vol. 219 No. 11 e201909073 during uptake and degradation of either extracellular fluids for autophagy and other cellular processes. However, the or particles by macropinocytosis or phagocytosis, respectively phosphatases that regulate autophagy remain largely unex- (Zoncu et al., 2009), and phagosome maturation coincides with plored. We sought to identify novel phosphatases that regulate PI(3)P reduction (Levin et al., 2015). Likewise, autophagy pro- autophagy by screening the Drosophila PI phosphatases because gression from start to finish relies upon PI identity changes. of their links to membrane trafficking and autophagy. We used Autophagy initiation requires recruitment of the class III PI3K the flippase/flippase-recognition target (FLP/FRT) system (Golic complex I to preautophagosomal structures (Funderburk et al., and Lindquist, 1989; Theodosiou and Xu, 1998)tosimultaneously 2010), which results in PI(3)P production and recruitment of express GFP and RNAi that target phosphatases in clones of cells autophagosome-forming effectors (Lystad and Simonsen, 2016). within tissues that uniformly express the autophagy reporter Meanwhile, autophagosome–lysosome fusion requires multiple mCherry-Atg8a. PI conversion events. For example, fusion requires production of Drosophila larval intestine enterocytes contain pmCherry- PI(4)P at autophagosomes by PIK4IIα (Wang et al., 2015), as well Atg8apuncta2hafterpupariumformation(APF)duetohigh Downloaded from http://rupress.org/jcb/article-pdf/219/11/e201909073/1049533/jcb_201909073.pdf by Massachusetts Worcester user on 10 January 2021 as lysosomal PI(3,5)P2 synthesis by PIKFYVE (de Lartigue et al., levels of developmental autophagy (Denton et al., 2009). 2009) and hydrolysis by INPP5E (Hasegawa et al., 2016). After Therefore, we evaluated the effects of PI phosphatase RNAi on fusion, a transient PIP5K-mediated PI(4,5)P2 increase on the mCherry-Atg8a expression in 2-h-APF midguts (Table S1). We lysosomal surface recruits clathrin machinery (Rong et al., 2012), identified multiple previously described regulators of au- which is followed by inositol polyphosphate-5-phosphatase tophagy, such as PTEN (not shown), as well as CG3530/Mtmr6 (OCRL)-mediated PI(4,5)P2 turnover to PI(4)P for autophagic (dMtmr6 hereafter), a previously undescribed regulator of lysosome reformation (De Leo et al., 2016). autophagy. Expression of double-stranded RNA targeting Both PI(3)P and PI(3,5)P2 facilitate degradative membrane- dMtmr6 generates cells that contain Atg8a puncta in feeding driven cellular processes. Thus, as described above, enzymes third-instar larvae (L3) when autophagy remains inactive in that catalyze their synthesis or turnover play critical roles neighboring WT cells (Fig. 1, A and B). At 2 h APF, dMtmr6- in trafficking membrane-bound cargoes to the lysosome. knockdown enterocytes contain both increased and enlarged Myotubularin-related phosphatases (MTMRs) are a conserved mCherry-Atg8a puncta compared with neighboring
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