AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts

Masaru Kato; Caroline Ospelt; Christoph Kolling; Tomohiro Shimizu; Michihito Kono; Shinsuke Yasuda; Beat A Michel; Renate E Gay; Steffen Gay; Kerstin Klein; Tatsuya Atsumi

doi:10.18632/oncotarget.11890

AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts

Oncotarget. 2016 Sep 27;7(39):64221-64232. doi: 10.18632/oncotarget.11890.

Authors

Affiliations

¹ Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
² Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
³ Schulthess Clinic, Zurich, Switzerland.
⁴ Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Abstract

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.

Keywords: autophagy; cell death; histone deacetylase 6; p97; polyubiquitin.

MeSH terms

Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism*
Animals
Apoptosis*
Arthritis, Experimental / enzymology
Arthritis, Experimental / genetics
Arthritis, Experimental / pathology
Arthritis, Experimental / therapy
Arthritis, Rheumatoid / enzymology*
Arthritis, Rheumatoid / genetics
Arthritis, Rheumatoid / pathology
Arthritis, Rheumatoid / therapy
Autophagy*
Cell Proliferation
Cells, Cultured
Female
Fibroblasts / enzymology*
Fibroblasts / pathology
Histone Deacetylase 6 / genetics
Histone Deacetylase 6 / metabolism
Humans
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Polyubiquitin
RNA Interference
RNAi Therapeutics
Rats, Inbred Lew
Signal Transduction
Synovial Membrane / enzymology*
Synovial Membrane / pathology
Time Factors
Transfection
Ubiquitination
Valosin Containing Protein / genetics
Valosin Containing Protein / metabolism*

Substances

Nuclear Proteins
Polyubiquitin
HDAC6 protein, human
Histone Deacetylase 6
Adenosine Triphosphatases
p97 ATPase
VCP protein, human
Valosin Containing Protein
Vcp protein, rat