TNF‐α increases ubiquitin‐conjugating activity in skeletal muscle by up‐regulating UbcH2/E220k

YP Li, SH Lecker, Y Chen, ID Waddell… - The FASEB …, 2003 - Wiley Online Library
YP Li, SH Lecker, Y Chen, ID Waddell, AL Goldberg, MB Reid
The FASEB journal, 2003Wiley Online Library
In some inflammatory diseases, TNF‐α is thought to stimulate muscle catabolism via an NF‐
κB‐dependent process that increases ubiquitin conjugation to muscle proteins. The
transcriptional mechanism of this response has not been determined. Here we studied the
potential role of UbcH2, a ubiquitin carrier protein and homologue of murine E220k. We find
that UbcH2 is constitutively expressed by human skeletal and cardiac muscles, murine limb
muscle, and cultured myotubes. TNF‐α stimulates UbcH2 expression in mouse limb muscles …
Abstract
In some inflammatory diseases, TNF‐α is thought to stimulate muscle catabolism via an NF‐κB‐dependent process that increases ubiquitin conjugation to muscle proteins. The transcriptional mechanism of this response has not been determined. Here we studied the potential role of UbcH2, a ubiquitin carrier protein and homologue of murine E220k. We find that UbcH2 is constitutively expressed by human skeletal and cardiac muscles, murine limb muscle, and cultured myotubes. TNF‐α stimulates UbcH2 expression in mouse limb muscles in vivo and in cultured myotubes. The UbcH2 promoter region contains a functional NF‐κB binding site;NF‐κB binding to this sequence is increased by TNF‐α stimulation. A dominant negative inhibitor of NF‐κB activation blocks both UbcH2 up‐regulation and the increase in ubiquitin‐conjugating activity stimulated by TNF‐α. In extracts from TNF‐α‐treated myotubes, ubiquitin‐conjugating activity is limited by UbcH2 availability; activity is inhibited by an antiserum to UbcH2 or a dominant negative mutant of UbcH2 and is enhanced by wild‐type UbcH2. Thus, UbcH2 up‐regulation is a novel response to TNF‐α/NF‐κB signaling in skeletal muscle that appears to be essential for the increased ubiquitin conjugation induced by this cytokine.—Y.‐P.Li, S. H.Lecker, Y.Chen, I. D.Waddell, A. L.Goldberg, M. B.Reid TNF‐α increases ubiquitin‐conjugating activity in skeletal muscle by up‐regulating UbcH2/E220k. FASEB J. 17, 1048–1057 (2003)
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