Ubiquitin activated tumor necrosis factor receptor associated factor-6 (TRAF6) is recycled via deubiquitination.
Ubiquitination of intermediates in the interleukin-1 (IL-1) signaling cascade plays an important role in activation and regulation of the pathway. Both IL-1 receptor associated kinase-1 (IRAK1) and inhibitor of nuclear factor kappaB-alpha (IkappaBalpha) are rapidly ubiquitinated and degraded. Tumor necrosis factor associated factor-6 (TRAF6) is an ubiquitin ligase that is activated by ubiquitination and a signaling intermediate between IRAK1 and IkappaBalpha. It is unknown whether activated TRAF6 is subsequently degraded. We show that in liver cells IL-1 stimulates TRAF6 poly-ubiquitination. In less than 1 h levels of non-modified TRAF6 return to levels near those observed prior to activation. TRAF6 cannot be reactivated in cells which have been pretreated with IL-1. This observation correlates with decreased levels of IRAK1 in IL-1 pretreated cells. The re-establishment of non-modified TRAF6 levels following activation does not require de novo protein synthesis, strongly suggesting that TRAF6 is recycled via deubiquitination. This indicates a unique mechanism of regulation of TRAF6 activity.
Jensen
Liselotte E
LE
Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA. jensen@pharm.med.upenn.edu
Whitehead
Alexander S
AS
D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D011506:Proteins / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*
D020672:I-kappa B Proteins; D007375:Interleukin-1; C000606204:NFKBIA protein, human; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha