DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation
The endoplasmic reticulum (ER) fills the cell with a continuous network of sealed membrane tubules and sheets. The ER is subdivided into microdomains mediating one-third of total protein biosynthesis, oxidative protein folding, secretion, protein quality control, calcium signaling, marcoautophagy/au...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Autophagy Reports |
| Online Access: | http://dx.doi.org/10.1080/27694127.2022.2139335 |
| _version_ | 1797685703090372608 |
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| author | Andrew Kennedy Douglas M. Cyr |
| author_facet | Andrew Kennedy Douglas M. Cyr |
| author_sort | Andrew Kennedy |
| collection | DOAJ |
| description | The endoplasmic reticulum (ER) fills the cell with a continuous network of sealed membrane tubules and sheets. The ER is subdivided into microdomains mediating one-third of total protein biosynthesis, oxidative protein folding, secretion, protein quality control, calcium signaling, marcoautophagy/autophagy, stress sensing, and apoptosis. Defects in ER-calcium homeostasis underlie several diseases. Damage to the ER by misfolded membrane proteins is suppressed by specific HSPA/Hsp70 and DNAJ/Hsp40 chaperone pairs that select intermediates for ubiquitination and ER-associated degradation (ERAD) via the proteasome. The ER-transmembrane Hsp40 chaperone DNAJB12 and HSPA/Hsp70 also target toxic intermediates of misfolded membrane proteins for ER-associated autophagy (ERAA). DNAJB12-HSPA/Hsp70 maintain membrane protein degradation intermediates in detergent-soluble and degradation-competent states. DNAJB12-HSPA/Hsp70 also interact with the autophagy initiation kinase ULK1 on ER tubules containing ERAD-resistant misfolded membrane proteins (ERAD-RMPs). Omegasomes are ER microdomains where the autophagosome precursor or phagophore (PG) forms. ER tubules loaded with ERAD-RMPs enter omegasomes where they are converted into ER-connected PG (ER-PG). The Atg8 (autophagy related 8)-family member GABARAP (GABA type A receptor-associated protein) facilitates transfer of ERAD-RMPs from ER-PGs to autolysosomes (AL) that dock transiently with omegasomes. This article describes a model for DNAJB12-HSPA/Hsp70 action during the conformation-dependent triage in the ER of misfolded membrane proteins for folding versus proteasomal or AL degradation. Abbreviations: ABC-transporter, ATP binding cassette transporter; Atg8, autophagy related 8; DNAJB12, DnaJ heat shock protein family (Hsp40) member B12; ER, endoplasmic reticulum; ERAD, ER-associated proteasomal degradation; ERAA, ER-associated autophagy; ERAD-RMPs, ER-associated proteasomal degradation resistant membrane protein; GABARAP, GABA type A receptor-associated protein; GPCR, G protein-coupled receptor; HSPA/Hsp70, heat shock protein family A (Hsp70); LAMP1, lysosomal associated membrane protein 1; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; P-type ATPases, ion transporting ATPase; ULK1, unc-51 like autophagy activating kinase 1; RB1CC1/FIP200, RB1 inducible coiled-coil 1; WIPI, WD repeat domain, phosphoinositide interacting. |
| first_indexed | 2024-03-12T00:55:07Z |
| format | Article |
| id | doaj.art-58e4d1bb36b74c3097f56d1cb8648990 |
| institution | Directory Open Access Journal |
| issn | 2769-4127 |
| language | English |
| last_indexed | 2024-03-12T00:55:07Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj.art-58e4d1bb36b74c3097f56d1cb86489902023-09-14T13:24:40ZengTaylor & Francis GroupAutophagy Reports2769-41272022-12-011155956210.1080/27694127.2022.21393352139335DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal DegradationAndrew Kennedy0Douglas M. Cyr1Marsico Lung Institute, School of Medicine, the University of North Carolina at Chapel HillMarsico Lung Institute, School of Medicine, the University of North Carolina at Chapel HillThe endoplasmic reticulum (ER) fills the cell with a continuous network of sealed membrane tubules and sheets. The ER is subdivided into microdomains mediating one-third of total protein biosynthesis, oxidative protein folding, secretion, protein quality control, calcium signaling, marcoautophagy/autophagy, stress sensing, and apoptosis. Defects in ER-calcium homeostasis underlie several diseases. Damage to the ER by misfolded membrane proteins is suppressed by specific HSPA/Hsp70 and DNAJ/Hsp40 chaperone pairs that select intermediates for ubiquitination and ER-associated degradation (ERAD) via the proteasome. The ER-transmembrane Hsp40 chaperone DNAJB12 and HSPA/Hsp70 also target toxic intermediates of misfolded membrane proteins for ER-associated autophagy (ERAA). DNAJB12-HSPA/Hsp70 maintain membrane protein degradation intermediates in detergent-soluble and degradation-competent states. DNAJB12-HSPA/Hsp70 also interact with the autophagy initiation kinase ULK1 on ER tubules containing ERAD-resistant misfolded membrane proteins (ERAD-RMPs). Omegasomes are ER microdomains where the autophagosome precursor or phagophore (PG) forms. ER tubules loaded with ERAD-RMPs enter omegasomes where they are converted into ER-connected PG (ER-PG). The Atg8 (autophagy related 8)-family member GABARAP (GABA type A receptor-associated protein) facilitates transfer of ERAD-RMPs from ER-PGs to autolysosomes (AL) that dock transiently with omegasomes. This article describes a model for DNAJB12-HSPA/Hsp70 action during the conformation-dependent triage in the ER of misfolded membrane proteins for folding versus proteasomal or AL degradation. Abbreviations: ABC-transporter, ATP binding cassette transporter; Atg8, autophagy related 8; DNAJB12, DnaJ heat shock protein family (Hsp40) member B12; ER, endoplasmic reticulum; ERAD, ER-associated proteasomal degradation; ERAA, ER-associated autophagy; ERAD-RMPs, ER-associated proteasomal degradation resistant membrane protein; GABARAP, GABA type A receptor-associated protein; GPCR, G protein-coupled receptor; HSPA/Hsp70, heat shock protein family A (Hsp70); LAMP1, lysosomal associated membrane protein 1; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; P-type ATPases, ion transporting ATPase; ULK1, unc-51 like autophagy activating kinase 1; RB1CC1/FIP200, RB1 inducible coiled-coil 1; WIPI, WD repeat domain, phosphoinositide interacting.http://dx.doi.org/10.1080/27694127.2022.2139335 |
| spellingShingle | Andrew Kennedy Douglas M. Cyr DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation Autophagy Reports |
| title | DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation |
| title_full | DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation |
| title_fullStr | DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation |
| title_full_unstemmed | DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation |
| title_short | DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation |
| title_sort | dnajb12 and hsp70 mediate triage of misfolded membrane proteins for proteasomal versus lysosomal degradation |
| url | http://dx.doi.org/10.1080/27694127.2022.2139335 |
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