title: The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2.
abstract: The inhibitors of apoptosis (IAPs) are critical regulators of apoptosis and other fundamental cellular processes. Many IAPs are RING domain-containing ubiquitin E3 ligases that control the stability of their interacting proteins. However, how IAP stability is regulated remains unclear. Here we report that USP19, a deubiquitinating enzyme, interacts with cellular IAP 1 (c-IAP1) and c-IAP2. Knockdown of USP19 decreases levels of both c-IAPs, whereas overexpression of USP19 results in a marked increase in c-IAP levels. USP19 effectively removes ubiquitin from c-IAPs in vitro, but it stabilizes c-IAPs in vivo mainly through deubiquitinase-independent mechanisms. The deubiquitinase activity is involved in the stabilization of USP19 itself, which is facilitated by USP19 self-association. Functionally, knockdown of USP19 enhances TNFα-induced caspase activation and apoptosis in a c-IAP1 and 2-dependent manner. These results suggest that the self-ubiquitin ligase activity of c-IAPs is inhibited by USP19 and implicate deubiquitinating enzymes in the regulation of IAP stability.
authors.affiliation: Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Yide
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Allison Alcivar
authors.initials: AA
authors.lastname: Hahn
authors.affiliation: Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Shimin
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: xyang@mail.med.upenn.edu.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yang
mesh_terms: D020169:Caspases / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D010450:Endopeptidases; C559917:USP19 protein, human; D020169:Caspases