ZNF451 is a novel PML body- and SUMO-associated transcriptional coregulator.
Covalent modification by small ubiquitin-related modifiers (SUMOs) is an important means to regulate dynamic residency of transcription factors within nuclear compartments. Here, we identify a multi-C(2)H(2)-type zinc finger protein (ZNF), ZNF451, as a novel nuclear protein that can be associated with promyelocytic leukemia bodies. In keeping with its interaction with SUMO E2 conjugase Ubc9 and SUMOs, ZNF451 is covalently modified by SUMOs (sumoylated) at several, albeit nonconsensus, sites. Interestingly, noncovalent SUMO-binding activity of ZNF451 (SUMO-interacting motif) is also important for its sumoylation. SUMO modifications regulate the nuclear compartmentalization of ZNF451, since coexpression of ZNF451 with SUMO-specific proteases SENP1 or SENP2, both capable of desumoylating the protein, redistributes ZNF451 from nuclear domains to speckles and nucleoplasm. Interaction of ZNF451 with PIAS1 (protein inhibitor of activated STAT 1) is not manifested as PIAS1's E3 SUMO ligase activity towards ZNF451 but results in disintegration of ZNF451 nuclear domains and recruitment of ZNF451 to androgen receptor (AR) speckles. ZNF451 interacts weakly, but in a SUMO-1-enhanced fashion, with AR. ZNF451 does not harbor an intrinsic transcription activation function, but interestingly, ablation of endogenous ZNF451 in prostate cancer cells significantly decreases expression of several AR target genes. Thus, we suggest that ZNF451 exerts its effects via SUMO modification machinery and trafficking of transcription regulators between promyelocytic leukemia bodies and nucleoplasm.
Karvonen
Ulla
U
Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, P.O. Box 63, FI-00014, Helsinki, Finland.
Jääskeläinen
Tiina
T
Rytinki
Miia
M
Kaikkonen
Sanna
S
Palvimo
Jorma J
JJ
D019881:Aminoacyltransferases; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011487:Protein Conformation; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D050828:Protein Inhibitors of Activated STAT; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D019881:Aminoacyltransferases; C531551:ZNF451 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D010450:Endopeptidases; D010447:Peptide Hydrolases; C404512:SENP1 protein, human; C512579:Senp5 protein, human; D003546:Cysteine Endopeptidases; D000098843:Ubiquitin-Conjugating Enzyme UBC9