AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts
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Masaru Kato1, Caroline Ospelt2, Christoph Kolling3, Tomohiro Shimizu4, Michihito Kono1, Shinsuke Yasuda1, Beat A. Michel2, Renate E. Gay2, Steffen Gay2, Kerstin Klein2,*, Tatsuya Atsumi1,*
1Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
2Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
3Schulthess Clinic, Zurich, Switzerland
4Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
*These authors contributed equally to this work
Masaru Kato, email: [email protected]
Keywords: p97, histone deacetylase 6, polyubiquitin, cell death, autophagy
Received: November 30, 2015 Accepted: September 02, 2016 Published: September 07, 2016
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.
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