Nitric oxide destabilizes Pias3 and regulates sumoylation.
Small ubiquitin-related protein modifiers (SUMO) modification is an important mechanism for posttranslational regulation of protein function. However, it is largely unknown how the sumoylation pathway is regulated. Here, we report that nitric oxide (NO) causes global hyposumoylation in mammalian cells. Both SUMO E2 conjugating enzyme Ubc9 and E3 ligase protein inhibitor of activated STAT3 (Pias3) were targets for S-nitrosation. S-nitrosation did not interfere with the SUMO conjugating activity of Ubc9, but promoted Pias3 degradation by facilitating its interaction with tripartite motif-containing 32 (Trim32), a ubiquitin E3 ligase. On the one hand, NO promoted Trim32-mediated Pias3 ubiquitination. On the other hand, NO enhanced the stimulatory effect of Pias3 on Trim32 autoubiquitination. The residue Cys459 of Pias3 was identified as a target site for S-nitrosation. Mutation of Cys459 abolished the stimulatory effect of NO on the Pias3-Trim32 interaction, indicating a requirement of S-nitrosation at Cys459 for positive regulation of the Pias3-Trim32 interplay. This study reveals a novel crosstalk between S-nitrosation, ubiquitination, and sumoylation, which may be crucial for NO-related physiological and pathological processes.
Qu
Jing
J
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Beijing, China.
Liu
Guang-Hui
GH
Wu
Kaiyuan
K
Han
Peiwei
P
Wang
Peng
P
Li
Jiangmei
J
Zhang
Xu
X
Chen
Chang
C
D020816:Amino Acid Motifs; D003545:Cysteine / Q000737:chemistry; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry; D014162:Transfection; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases; D003545:Cysteine