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Endoplasmic reticulum stress–induced degradation of DNAJB12 stimulates BOK accumulation and primes cancer cells for apoptosis
- Publication Year :
- 2017
- Publisher :
- The University of North Carolina at Chapel Hill University Libraries, 2017.
-
Abstract
- DNAJB12 (JB12) is an endoplasmic reticulum (ER)-associated Hsp40 family protein that recruits Hsp70 to the ER surface to coordinate the function of ER-associated and cytosolic chaperone systems in protein quality control. Hsp70 is stress-inducible, but paradoxically, we report here that JB12 was degraded by the proteasome during severe ER stress. Destabilized JB12 was degraded by ER-associated degradation complexes that contained HERP, Sel1L, and gp78. JB12 was the only ER-associated chaperone that was destabilized by reductive stress. JB12 knockdown by siRNA led to the induction of caspase processing but not the unfolded protein response. ER stress-induced apoptosis is regulated by the highly labile and ER-associated BCL-2 family member BOK, which is controlled at the level of protein stability by ER-associated degradation components. We found that JB12 was required in human hepatoma cell line 7 (Huh-7) liver cancer cells to maintain BOK at low levels, and BOK was detected in complexes with JB12 and gp78. Depletion of JB12 during reductive stress or by shRNA from Huh-7 cells was associated with accumulation of BOK and activation of Caspase 3, 7, and 9. The absence of JB12 sensitized Huh-7 to death caused by proteotoxic agents and the proapoptotic chemotherapeutic LCL-161. In summary, JB12 is a stress-sensitive Hsp40 whose degradation during severe ER stress provides a mechanism to promote BOK accumulation and induction of apoptosis.
- Subjects :
- 0301 basic medicine
Proteasome Endopeptidase Complex
Carcinoma, Hepatocellular
Recombinant Fusion Proteins
Antineoplastic Agents
Apoptosis
Caspase 3
Biochemistry
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Chlorocebus aethiops
Animals
Humans
Molecular Biology
Caspase
biology
Protein Stability
Endoplasmic reticulum
Liver Neoplasms
Cell Biology
HSP40 Heat-Shock Proteins
Endoplasmic Reticulum Stress
Neoplasm Proteins
Cell biology
Receptors, Autocrine Motility Factor
Thiazoles
HEK293 Cells
030104 developmental biology
Proteostasis
Amino Acid Substitution
Proto-Oncogene Proteins c-bcl-2
Proteasome
Protein Synthesis and Degradation
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Chaperone (protein)
COS Cells
Mutation
Proteolysis
Cancer cell
biology.protein
Unfolded protein response
RNA Interference
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....035f2b4f9eacd0d93d63851b7884f0f6
- Full Text :
- https://doi.org/10.17615/8nf9-qe71