Proteaphagy in Mammalian Cells Can Function Independent of ATG5/ATG7

Abstract

The degradation of intra- and extracellular proteins is essential in all cell types and mediated by two systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. This study investigates the changes in autophagosomal and lysosomal proteomes upon inhibition of proteasomes by bortezomib (BTZ) or MG132. We find an increased abundance of more than 50 proteins in lysosomes of cells in which the proteasome is inhibited. Among those are dihydrofolate reductase (DHFR), β-Catenin and 3-hydroxy-3-methylglutaryl-coenzym-A (HMGCoA)-reductase. Because these proteins are known to be degraded by the proteasome they seem to be compensatorily delivered to the autophagosomal pathway when the proteasome is inactivated. Surprisingly, most of the proteins which show increased amounts in the lysosomes of BTZ or MG132 treated cells are proteasomal subunits. Thus an inactivated, non-functional proteasome is delivered to the autophagic pathway. Native gel electrophoresis shows that the proteasome reaches the lysosome intact and not disassembled. Adaptor proteins, which target proteasomes to autophagy, have been described in Arabidopsis, Saccharomyces and upon starvation in mammalians. However, in cell lines deficient of these proteins or their mammalian orthologues, respectively, the transfer of proteasomes to the lysosome is not impaired. Obviously, these proteins do not play a role as autophagy adaptor proteins in mammalian cells. We can also show that chaperone-mediated autophagy (CMA) does not participate in the proteasome delivery to the lysosomes. In autophagy-related (ATG)-5 and ATG7 deficient cells the delivery of inactivated proteasomes to the autophagic pathway was only partially blocked, indicating the existence of at least two different pathways by which inactivated proteasomes can be delivered to the lysosome in mammalian cells. The degradation of intra- and extracellular proteins is essential in all cell types and mediated by two systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. This study investigates the changes in autophagosomal and lysosomal proteomes upon inhibition of proteasomes by bortezomib (BTZ) or MG132. We find an increased abundance of more than 50 proteins in lysosomes of cells in which the proteasome is inhibited. Among those are dihydrofolate reductase (DHFR), β-Catenin and 3-hydroxy-3-methylglutaryl-coenzym-A (HMGCoA)-reductase. Because these proteins are known to be degraded by the proteasome they seem to be compensatorily delivered to the autophagosomal pathway when the proteasome is inactivated. Surprisingly, most of the proteins which show increased amounts in the lysosomes of BTZ or MG132 treated cells are proteasomal subunits. Thus an inactivated, non-functional proteasome is delivered to the autophagic pathway. Native gel electrophoresis shows that the proteasome reaches the lysosome intact and not disassembled. Adaptor proteins, which target proteasomes to autophagy, have been described in Arabidopsis, Saccharomyces and upon starvation in mammalians. However, in cell lines deficient of these proteins or their mammalian orthologues, respectively, the transfer of proteasomes to the lysosome is not impaired. Obviously, these proteins do not play a role as autophagy adaptor proteins in mammalian cells. We can also show that chaperone-mediated autophagy (CMA) does not participate in the proteasome delivery to the lysosomes. In autophagy-related (ATG)-5 and ATG7 deficient cells the delivery of inactivated proteasomes to the autophagic pathway was only partially blocked, indicating the existence of at least two different pathways by which inactivated proteasomes can be delivered to the lysosome in mammalian cells. Two distinct mechanisms, the autophagy-lysosome pathway and the UPS, mediate protein degradation within the cell. Lysosomes are membrane-bound organelles mediating the degradation of intracellular macromolecules like proteins, lipids and oligosaccharides. Endocytosed cargo and autophagocytosed cell components (1Saftig P. Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function.Nat. Rev. Mol. Cell Biol. 2009; 10: 623-635Crossref PubMed Scopus (1095) Google Scholar) are degraded by a wide array of acid hydrolases. The delivery of substrates to the lysosomal lumen is mostly accomplished by vesicle transport, through endosomes and phagosomes for extracellular material or autophagosomes for the degradation of intracellular material. Alternatively, lysosomal substrates can be delivered by CMA or endosomal microautophagy (2Tekirdag K. Cuervo A.M. Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone.J. Biol. Chem. 2018; 293: 5414-5424Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar). The generation of autophagosomes starts by the formation and growth of a double-layered isolation membrane enabled by specialized autophagy proteins like the microtubule-associated protein light chain 3 (LC3) 1The abbreviations used are:LC3microtubule-associated protein light chain 3ACNacetonitrileATGautophagy-relatedBOD-TMR-EpoxBodipy-TMR-epoxomycinBTZbortezomibCMAchaperone-mediated autophagyDHFRdihydrofolate reductaseHEKhuman embryonic kidneyHMGCoA3-hydroxy-3-methylglutaryl-Coenzyme AKEGGKyoto Encyclopedia of Genes and GenomesLAMPlysosome-associated membrane proteinMEFmouse embryonic fibroblastNBR1Neighbor of BRCA1 gene 1 proteinNCO4nuclear receptor coactivator 4NUFIP1nuclear FMR1-interacting protein 1PSMAproteasome subunit alphaPSMBproteasome subunit betaPSMCregulatory proteasome subunitPSMD26S proteasome regulatory subunitSILACstable isotope labeling in cell cultureSNARESsoluble N-ethylmaleimide-sensitive-factor attachment receptorsSQSTM1sequestosome-1/p62TOLLIPToll-interacting proteinUPSubiquitin-proteasome system. 1The abbreviations used are:LC3microtubule-associated protein light chain 3ACNacetonitrileATGautophagy-relatedBOD-TMR-EpoxBodipy-TMR-epoxomycinBTZbortezomibCMAchaperone-mediated autophagyDHFRdihydrofolate reductaseHEKhuman embryonic kidneyHMGCoA3-hydroxy-3-methylglutaryl-Coenzyme AKEGGKyoto Encyclopedia of Genes and GenomesLAMPlysosome-associated membrane proteinMEFmouse embryonic fibroblastNBR1Neighbor of BRCA1 gene 1 proteinNCO4nuclear receptor coactivator 4NUFIP1nuclear FMR1-interacting protein 1PSMAproteasome subunit alphaPSMBproteasome subunit betaPSMCregulatory proteasome subunitPSMD26S proteasome regulatory subunitSILACstable isotope labeling in cell cultureSNARESsoluble N-ethylmaleimide-sensitive-factor attachment receptorsSQSTM1sequestosome-1/p62TOLLIPToll-interacting proteinUPSubiquitin-proteasome system. in the cytoplasm, engulfing cargo that is to be degraded (3Bento C.F. Renna M. Ghislat G. Puri C. Ashkenazi A. Vicinanza M. Menzies F.M. Rubinsztein D.C. Mammalian Autophagy: How Does It Work?.Annu. Rev. Biochem. 2016; 85: 685-713Crossref PubMed Scopus (454) Google Scholar). This engulfment can be mediated by adaptor proteins for specific cargo in case of selective autophagy, as has been shown for ribosomes in case of the nuclear FMR1-interacting protein 1 (NUFIP1) (4Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google Scholar) or nuclear receptor coactivator 4 (NCOA4) (5Mancias J.D. Wang X. Gygi S.P. Harper J.W. Kimmelman A.C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.Nature. 2014; 509: 105-109Crossref PubMed Scopus (809) Google Scholar) for ferritin degradation, respectively. Often selective autophagy of a specific cargo is preceded by its ubiquitination, which in turn enables attachment to ubiquitin-binding domain-containing proteins like sequestosome-1/p62 (SQSTM1) or Neighbor of BRCA1 gene 1 protein (NBR1). After closing of the autophagosomal membrane, autophagosomes and lysosomes fuse by the action of several proteins like soluble N-ethylmaleimide-sensitive-factor attachment receptors (SNARES) (6Nakamura S. Yoshimori T. New insights into autophagosome-lysosome fusion.J. Cell Sci. 2017; 130: 1209-1216Crossref PubMed Scopus (308) Google Scholar) and the inner autophagosomal membrane including its content is degraded by lysosomal hydrolases. microtubule-associated protein light chain 3 acetonitrile autophagy-related Bodipy-TMR-epoxomycin bortezomib chaperone-mediated autophagy dihydrofolate reductase human embryonic kidney 3-hydroxy-3-methylglutaryl-Coenzyme A Kyoto Encyclopedia of Genes and Genomes lysosome-associated membrane protein mouse embryonic fibroblast Neighbor of BRCA1 gene 1 protein nuclear receptor coactivator 4 nuclear FMR1-interacting protein 1 proteasome subunit alpha proteasome subunit beta regulatory proteasome subunit 26S proteasome regulatory subunit isotope labeling in cell soluble N-ethylmaleimide-sensitive-factor attachment receptors sequestosome-1/p62 protein ubiquitin-proteasome system. microtubule-associated protein light chain 3 acetonitrile autophagy-related Bodipy-TMR-epoxomycin bortezomib chaperone-mediated autophagy dihydrofolate reductase human embryonic kidney 3-hydroxy-3-methylglutaryl-Coenzyme A Kyoto Encyclopedia of Genes and Genomes lysosome-associated membrane protein mouse embryonic fibroblast Neighbor of BRCA1 gene 1 protein nuclear receptor coactivator 4 nuclear FMR1-interacting protein 1 proteasome subunit alpha proteasome subunit beta regulatory proteasome subunit 26S proteasome regulatory subunit isotope labeling in cell soluble N-ethylmaleimide-sensitive-factor attachment receptors sequestosome-1/p62 protein ubiquitin-proteasome system. In to the organelles lysosomes and proteasomes as protein within the are of the 4 or in two of and and mediate the of the within the of the The regulatory can be into and and its mediate of substrates and the of of the into the of the proteasome of the 26S to Mol. PubMed Scopus Google Scholar). proteins and of their can only do when proteins are and their This is mediated by a action of the which the of and to the is to a of the target protein by specific of the A. A. The Rev. Biochem. PubMed Scopus Google Scholar). the system and the proteasome as two within the in has that those are as can proteins have been shown to be degraded by and an increased autophagic protein degradation in case of proteasome Menzies F.M. Rubinsztein D.C. of the ubiquitin-proteasome and autophagy-lysosome PubMed Scopus Google Scholar). 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NUFIP1 is a ribosome receptor for starvation-induced ribophagy.Science. 2018; 360: 751-758Crossref PubMed Scopus (187) Google and (6Nakamura S. Yoshimori T. New insights into autophagosome-lysosome fusion.J. Cell Sci. 2017; 130: 1209-1216Crossref PubMed Scopus (308) Google Scholar) (2Tekirdag K. Cuervo A.M. Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone.J. Biol. Chem. 2018; 293: 5414-5424Abstract Full Text Full Text PDF PubMed Scopus (198) Google labeling to two The was a of for the and for the and a of to and a of for the and for the The in was the specific protein of or the specific protein of was as by for of for which and and was as by The proteomics have been to the the (1Saftig P. Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function.Nat. Rev. Mol. 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