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.
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Masaru
M
Kato
Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Caroline
C
Ospelt
Schulthess Clinic, Zurich, Switzerland.
Christoph
C
Kolling
Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tomohiro
T
Shimizu
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Michihito
M
Kono
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Shinsuke
S
Yasuda
Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Beat A
BA
Michel
Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Renate E
RE
Gay
Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Steffen
S
Gay
Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Kerstin
K
Klein
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tatsuya
T
Atsumi
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D001343:Autophagy; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D000073864:Histone Deacetylase 6 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin; D034622:RNA Interference; D000067492:RNAi Therapeutics; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D013583:Synovial Membrane / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D000074405:Valosin Containing Protein / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D025821:Polyubiquitin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D000251:Adenosine Triphosphatases; C404942:p97 ATPase; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614180:Vcp protein, rat
autophagy; cell death; histone deacetylase 6; p97; polyubiquitin