Regulation of homeodomain-interacting protein kinase 2 (HIPK2) effector function through dynamic small ubiquitin-related modifier-1 (SUMO-1) modification.
Homeodomain-interacting protein kinase 2 (HIPK2) is involved in transcriptional regulation, growth suppression, and apoptosis. Previous reports showed that HIPK2 can signal cell death via p53, and independently of p53 by activating the c-Jun NH2-terminal kinase (JNK) pathway or mediating CtBP degradation. Here we demonstrate that human HIPK2 is small ubiquitin-related modifier-1 (SUMO-1)-modified in vitro and in vivo at lysine residue 25, a SUMO consensus modification motif conserved in human and mouse HIPK family proteins. SUMO modification of HIPK2 altered neither its nuclear body localization nor its recruitment to promyelocytic leukemia-nuclear bodies. However, SUMO-1 modification inhibited HIPK2-induced JNK activation and p53-independent antiproliferative function. HIPK2 with a mutated SUMO acceptor lysine residue was refractory to inhibition of HIPK2-mediated JNK activation by SUMO-1. Furthermore, we demonstrate that SUMO protease SuPr-1 interacts with HIPK2, and both proteins predominantly colocalize in promyelocytic leukemia-nuclear bodies. SuPr-1 deconjugates SUMO-1 from HIPK2 in vitro and in vivo, which results in modestly increased HIPK2-induced JNK activity. Thus, our data demonstrate that HIPK2 effector function on JNK is modulated through dynamic SUMO-1 modification.
Hofmann
Thomas G
TG
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistrasse 52, 20251 Hamburg, Germany. t.hofmann@dkfz.de
Jaffray
Ellis
E
Stollberg
Nicole
N
Hay
Ronald T
RT
Will
Hans
H
D020816:Amino Acid Motifs; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008156:Luciferases / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D025842:SUMO-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D002352:Carrier Proteins; D025842:SUMO-1 Protein; D008156:Luciferases; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D008239:Lysine