AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts.
Valosin containing protein (p97) is a chaperone implicated in a large number of biological processes including endoplasmic reticulum (ER)-associated protein degradation and autophagy. Silencing of p97 in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) increased the amount of polyubiquitinated proteins, whereas silencing of its interaction partner histone deacetylase 6 (HDAC6) had ... no effect. Furthermore, silencing of p97 in RASFs increased not only rates of apoptotic cell death induced by TRAIL but also induced an autophagy-associated cell death during ER stress that was accompanied by the formation of polyubiquitinated protein aggregates and large vacuoles. Finally, we demonstrated an anti-arthritic effect of siRNAs targeting p97 in collagen-induced arthritis in rats. Our data indicate that p97 may be a new potential target in the treatment of RA.
Mesh Terms:
Adenosine Triphosphatases, Animals, Apoptosis, Arthritis, Experimental, Arthritis, Rheumatoid, Autophagy, Cell Proliferation, Cells, Cultured, Female, Fibroblasts, Histone Deacetylase 6, Humans, Nuclear Proteins, Polyubiquitin, RNA Interference, RNAi Therapeutics, Rats, Inbred Lew, Signal Transduction, Synovial Membrane, Time Factors, Transfection, Ubiquitination, Valosin Containing Protein
Adenosine Triphosphatases, Animals, Apoptosis, Arthritis, Experimental, Arthritis, Rheumatoid, Autophagy, Cell Proliferation, Cells, Cultured, Female, Fibroblasts, Histone Deacetylase 6, Humans, Nuclear Proteins, Polyubiquitin, RNA Interference, RNAi Therapeutics, Rats, Inbred Lew, Signal Transduction, Synovial Membrane, Time Factors, Transfection, Ubiquitination, Valosin Containing Protein
Oncotarget
Date: Sep. 27, 2016
PubMed ID: 27623077
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