Caspase-3 cleaves specific 19 S proteasome subunits in skeletal muscle stimulating proteasome activity.
With muscle wasting, caspase-3 activation and the ubiquitin-proteasome system act synergistically to increase the degradation of muscle proteins. Whether proteasome activity is also elevated in response to catabolic conditions is unknown. We find that caspase-3 increases proteasome activity in myotubes but not in myoblasts. This difference is related to the cleavage of specific 19 S proteasome subunits. In mouse muscle or myotubes, caspase-3 cleaves Rpt2 and Rpt6 increasing proteasome activity. In myoblasts, caspase-3 cleaves Rpt5 to decrease proteasome activity. To confirm the caspase-3 dependence, caspase-3 cleavage sites in Rpt2, Rpt6, or Rpt5 were mutated. This prevented the cleavage of these subunits by caspase-3 as well as the changes in proteasome activity. During differentiation of myoblasts to myotubes, there is an obligatory, transient increase in caspase-3 activity, accompanied by a corresponding increase in proteasome activity and cleavage of Rpt2 and Rpt6. Therefore, differentiation changes the proteasome type from sensitivity of Rpt5 to caspase-3 in myoblasts to sensitivity of Rpt2 and Rpt6 in myotubes. This novel mechanism identifies a feed-forward amplification that augments muscle proteolysis in catabolic conditions. Indeed, we found that in mice with a muscle wasting condition, chronic kidney disease, there was cleavage of subunits Rpt2 and Rpt6 and stimulation of proteasome activity.
Wang
Xiaonan H
XH
Renal Division, Emory University, Atlanta, Georgia 30322, USA. xwang03@emory.edu
Zhang
Liping
L
Mitch
William E
WE
LeDoux
Joseph M
JM
Hu
Junping
J
Du
Jie
J
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000201:enzymology*; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012335:RNA, Ribosomal / Q000737:chemistry* / Q000378:metabolism
D012335:RNA, Ribosomal; C097639:RNA, ribosomal, 19S; D000255:Adenosine Triphosphate; D010447:Peptide Hydrolases; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease