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LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization.

ABSTRACT:

Abbreviations

A253-control: A253 control for LAMP3 stable overexpression; A253- LAMP3: A253 LAPM3 stable overexpression; CASP1: caspase 1; CASP3: caspase 3; CHX: cycloheximide; CTSB: cathepsin B; CTSD: cathepsin D; CQ: chloroquine; DCs: dendritic cells; ER: endoplasmic reticulum; LGALS3: galectin 3; HCV: hepatitis C virus; HSG-control: HSG control for LAMP3 stable overexpression; HSG-LAMP3: HSG LAMP3 stable overexpression; HSP: heat shock protein; HTLV-1: human T-lymphocyte leukemia virus-1; IXA: ixazomib; LAMP: lysosomal associated membrane protein; MHC: major histocompatibility complex; mAb: monoclonal antibody; OE: overexpression; pepA: pepstatin A; pAb: polyclonal antibody; pSS: primary Sjögren syndrome; qRT-PCR: quantitative real- time reverse transcriptase polymerase chain reaction; SLE: systemic lupus erythematosus; SS: Sjögren syndrome; UPR: unfolded protein response; V-ATPase: vacuolar-type proton- translocating ATPase; Y-VAD: Ac-YVAD-cmk; Z-DEVD; Z-DEVD-fmk; Z-VAD: Z-VAD- fmk.

SUBMITTER: Tanaka T

PROVIDER: S-EPMC9298453 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization.

Tanaka Tsutomu T Warner Blake M BM Michael Drew G DG Nakamura Hiroyuki H Odani Toshio T Yin Hongen H Atsumi Tatsuya T Noguchi Masayuki M Chiorini John A JA

Autophagy 20211122 7

<h4>Abbreviations</h4>A253-control: A253 control for LAMP3 stable overexpression; A253- LAMP3: A253 LAPM3 stable overexpression; CASP1: caspase 1; CASP3: caspase 3; CHX: cycloheximide; CTSB: cathepsin B; CTSD: cathepsin D; CQ: chloroquine; DCs: dendritic cells; ER: endoplasmic reticulum; LGALS3: galectin 3; HCV: hepatitis C virus; HSG-control: HSG control for LAMP3 stable overexpression; HSG-LAMP3: HSG LAMP3 stable overexpression; HSP: heat shock protein; HTLV-1: human T-lymphocyte leukemia viru ...[more]

PMID: 34802379

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Project description:Increasing evidence suggests that induction of lethal macroautophagy/autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of previous work, we demonstrate that pimozide and loperamide trigger an ATG5- and ATG7 (autophagy related 5 and 7)-dependent type of cell death that is significantly reduced with cathepsin inhibitors and the lipid reactive oxygen species (ROS) scavenger α-tocopherol in MZ-54 GBM cells. Global proteomic analysis after treatment with both drugs also revealed an increase of proteins related to lipid and cholesterol metabolic processes. These changes were accompanied by a massive accumulation of cholesterol and other lipids in the lysosomal compartment, indicative of impaired lipid transport/degradation. In line with these observations, pimozide and loperamide treatment were associated with a pronounced increase of bioactive sphingolipids including ceramides, glucosylceramides and sphingoid bases measured by targeted lipidomic analysis. Furthermore, pimozide and loperamide inhibited the activity of SMPD1/ASM (sphingomyelin phosphodiesterase 1) and promoted induction of lysosomal membrane permeabilization (LMP), as well as release of CTSB (cathepsin B) into the cytosol in MZ-54 wild-type (WT) cells. Whereas LMP and cell death were significantly attenuated in ATG5 and ATG7 knockout (KO) cells, both events were enhanced by depletion of the lysophagy receptor VCP (valosin containing protein), supporting a pro-survival function of lysophagy under these conditions. Collectively, our data suggest that pimozide and loperamide-driven autophagy and lipotoxicity synergize to induce LMP and cell death. The results also support the notion that simultaneous overactivation of autophagy and induction of LMP represents a promising approach for the treatment of GBM.Abbreviations: ACD: autophagic cell death; AKT1: AKT serine/threonine kinase 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; CERS1: ceramide synthase 1; CTSB: cathepsin B; CYBB/NOX2: cytochrome b-245 beta chain; ER: endoplasmatic reticulum; FBS: fetal bovine serum; GBM: glioblastoma; GO: gene ontology; HTR7/5-HT7: 5-hydroxytryptamine receptor 7; KD: knockdown; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAP: LC3-associated phagocytosis; LMP: lysosomal membrane permeabilization; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; RB1CC1: RB1 inducible coiled-coil 1; ROS: reactive oxygen species; RPS6: ribosomal protein S6; SMPD1/ASM: sphingomyelin phosphodiesterase 1; VCP/p97: valosin containing protein; WT: wild-type.

Dataset Information

LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization.

Abbreviations

Publications

LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization.

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