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ATM loss disrupts the autophagy-lysosomal pathway.
Autophagy. 2021 08; 17(8):1998-2010.A

Abstract

ATM (ataxia telangiectasia mutated) protein is found associated with multiple organelles including synaptic vesicles, endosomes and lysosomes, often in cooperation with ATR (ataxia telangiectasia and Rad3 related). Mutation of the ATM gene results in ataxia-telangiectasia (A-T), an autosomal recessive disorder with defects in multiple organs including the nervous system. Precisely how ATM deficiency leads to the complex phenotypes of A-T, however, remains elusive. Here, we reported that part of the connection may lie in autophagy and lysosomal abnormalities. We found that ATM was degraded through the autophagy pathway, while ATR was processed by the proteasome. Autophagy and lysosomal trafficking were both abnormal in atm-/- neurons and the deficits impacted cellular functions such as synapse maintenance, neuronal survival and glucose uptake. Upregulated autophagic flux was observed in atm-/- lysosomes, associated with a more acidic pH. Significantly, we found that the ATP6V1A (ATPase, H+ transporting, lysosomal V1 subunit A) proton pump was an ATM kinase target. In atm-/- neurons, lysosomes showed enhanced retrograde transport and accumulated in the perinuclear regions. We attributed this change to an unexpected physical interaction between ATM and the retrograde transport motor protein, dynein. As a consequence, SLC2A4/GLUT4 (solute carrier family 4 [facilitated glucose transporter], member 4) translocation to the plasma membrane was inhibited and trafficking to the lysosomes was increased, leading to impaired glucose uptake capacity. Together, these data underscored the involvement of ATM in a variety of neuronal vesicular trafficking processes, offering new and therapeutically useful insights into the pathogenesis of A-T.Abbreviations: 3-MA: 3-methyladenine; A-T: ataxia-telangiectasia; ALG2: asparagine-linked glycosylation 2 (alpha-1,3-mannosyltransferase); AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG5: autophagy related 5; ATM: ataxia telangiectasia mutated; ATP6V1A: ATPase, H+ transporting, lysosomal V1 subunit A; ATR: ataxia-telangiectasia and Rad3 related; BFA1: bafilomycin A1; CC3: cleaved-CASP3; CGN: cerebellar granule neuron; CLQ: chloroquine; CN: neocortical neuron; CTSB: cathepsin B; CTSD: cathepsin D; DYNLL1: the light chain1 of dynein; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; Etop: etoposide; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HBS: HEPES-buffered saline; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HOMER1: homer protein homolog 1; KU: KU-60019; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: LC3-phosphatidylethanolamine conjugate; Lyso: lysosome; LysopH-GFP: lysopHluorin-GFP; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule associated protein 2; MAPK14: mitogen-activated protein kinase 14; MAPK8/JNK1: mitogen-activated protein kinase 8; MCOLN1/TRPML1: mucolipin 1; OSBPL1A: oxysterol binding protein like 1A; PIKK: phosphatidylinositol 3 kinase related kinase; Rapa: rapamycin; RILP: rab interacting lysosomal protein; ROS: reactive oxygen species; SEM: standard error of mean; SLC2A4/GLUT4: solute carrier family 2 (facilitated glucose transporter), member 4; TSC2/tuberin: TSC complex subunit 2; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system; VE: VE-822; WCL: whole-cell lysate; WT: wild type.

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Authors+Show Affiliations

Cheng A
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong. Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong.
Tse KH
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong.
Chow HM
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong.
Gan Y
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong.
Song X
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong.
Ma F
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong.
Qian YXY
Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
She W
Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong.
Herrup K
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong. Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

MeSH

Adaptor Proteins, Signal TransducingAnimalsAtaxia Telangiectasia Mutated ProteinsAutophagosomesAutophagyHumansLysosomesMicePhagocytosisUbiquitin

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32757690

Citation

Cheng, Aifang, et al. "ATM Loss Disrupts the Autophagy-lysosomal Pathway." Autophagy, vol. 17, no. 8, 2021, pp. 1998-2010.
Cheng A, Tse KH, Chow HM, et al. ATM loss disrupts the autophagy-lysosomal pathway. Autophagy. 2021;17(8):1998-2010.
Cheng, A., Tse, K. H., Chow, H. M., Gan, Y., Song, X., Ma, F., Qian, Y. X. Y., She, W., & Herrup, K. (2021). ATM loss disrupts the autophagy-lysosomal pathway. Autophagy, 17(8), 1998-2010. https://doi.org/10.1080/15548627.2020.1805860
Cheng A, et al. ATM Loss Disrupts the Autophagy-lysosomal Pathway. Autophagy. 2021;17(8):1998-2010. PubMed PMID: 32757690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ATM loss disrupts the autophagy-lysosomal pathway. AU - Cheng,Aifang, AU - Tse,Kai-Hei, AU - Chow,Hei-Man, AU - Gan,Yunqiao, AU - Song,Xuan, AU - Ma,Fulin, AU - Qian,Yi Xuan Yvonne, AU - She,Weiyi, AU - Herrup,Karl, Y1 - 2020/08/14/ PY - 2020/8/8/pubmed PY - 2022/1/18/medline PY - 2020/8/8/entrez KW - Ataxia-telangiectasia KW - SLC2A4/GLUT4 KW - autophagy KW - lysosome KW - neurodegeneration KW - protein degradation KW - trafficking SP - 1998 EP - 2010 JF - Autophagy JO - Autophagy VL - 17 IS - 8 N2 - ATM (ataxia telangiectasia mutated) protein is found associated with multiple organelles including synaptic vesicles, endosomes and lysosomes, often in cooperation with ATR (ataxia telangiectasia and Rad3 related). Mutation of the ATM gene results in ataxia-telangiectasia (A-T), an autosomal recessive disorder with defects in multiple organs including the nervous system. Precisely how ATM deficiency leads to the complex phenotypes of A-T, however, remains elusive. Here, we reported that part of the connection may lie in autophagy and lysosomal abnormalities. We found that ATM was degraded through the autophagy pathway, while ATR was processed by the proteasome. Autophagy and lysosomal trafficking were both abnormal in atm-/- neurons and the deficits impacted cellular functions such as synapse maintenance, neuronal survival and glucose uptake. Upregulated autophagic flux was observed in atm-/- lysosomes, associated with a more acidic pH. Significantly, we found that the ATP6V1A (ATPase, H+ transporting, lysosomal V1 subunit A) proton pump was an ATM kinase target. In atm-/- neurons, lysosomes showed enhanced retrograde transport and accumulated in the perinuclear regions. We attributed this change to an unexpected physical interaction between ATM and the retrograde transport motor protein, dynein. As a consequence, SLC2A4/GLUT4 (solute carrier family 4 [facilitated glucose transporter], member 4) translocation to the plasma membrane was inhibited and trafficking to the lysosomes was increased, leading to impaired glucose uptake capacity. Together, these data underscored the involvement of ATM in a variety of neuronal vesicular trafficking processes, offering new and therapeutically useful insights into the pathogenesis of A-T.Abbreviations: 3-MA: 3-methyladenine; A-T: ataxia-telangiectasia; ALG2: asparagine-linked glycosylation 2 (alpha-1,3-mannosyltransferase); AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG5: autophagy related 5; ATM: ataxia telangiectasia mutated; ATP6V1A: ATPase, H+ transporting, lysosomal V1 subunit A; ATR: ataxia-telangiectasia and Rad3 related; BFA1: bafilomycin A1; CC3: cleaved-CASP3; CGN: cerebellar granule neuron; CLQ: chloroquine; CN: neocortical neuron; CTSB: cathepsin B; CTSD: cathepsin D; DYNLL1: the light chain1 of dynein; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; Etop: etoposide; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HBS: HEPES-buffered saline; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HOMER1: homer protein homolog 1; KU: KU-60019; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: LC3-phosphatidylethanolamine conjugate; Lyso: lysosome; LysopH-GFP: lysopHluorin-GFP; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule associated protein 2; MAPK14: mitogen-activated protein kinase 14; MAPK8/JNK1: mitogen-activated protein kinase 8; MCOLN1/TRPML1: mucolipin 1; OSBPL1A: oxysterol binding protein like 1A; PIKK: phosphatidylinositol 3 kinase related kinase; Rapa: rapamycin; RILP: rab interacting lysosomal protein; ROS: reactive oxygen species; SEM: standard error of mean; SLC2A4/GLUT4: solute carrier family 2 (facilitated glucose transporter), member 4; TSC2/tuberin: TSC complex subunit 2; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system; VE: VE-822; WCL: whole-cell lysate; WT: wild type. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/32757690/ATM_loss_disrupts_the_autophagy_lysosomal_pathway_ DB - PRIME DP - Unbound Medicine ER -