Sumoylation-dependent control of homotypic and heterotypic synergy by the Kruppel-type zinc finger protein ZBP-89.
The Krüppel-like transcription factor ZBP-89 is a sequence-specific regulator that plays key roles in cellular growth and differentiation especially in endodermal and germ cell lineages. ZBP-89 shares with other members of the Sp-like family an overlapping sequence specificity for GC-rich sequences in the regulatory regions of multiple genes. Defining the mechanisms that govern the intrinsic function of ZBP-89 as well as its competitive and non-competitive functional interactions with other regulators is central to understand how ZBP-89 exerts its biological functions. We now describe that post-translational modification of ZBP-89 by multiple small ubiquitin-like modifier (SUMO) isoforms occurs at two conserved synergy control motifs flanking the DNA binding domain. Functionally sumoylation did not directly alter the ability of ZBP-89 to compete with other Sp-like factors from individual sites. At promoters bearing multiple response elements, however, this modification inhibited the functional cooperation between ZBP-89 and Sp1. Analysis of the properties of ZBP-89 in cellular contexts devoid of competing factors indicated that although on its own it behaves as a modest activator it potently synergizes with heterologous activators such as the glucocorticoid receptor. Notably we found that when conjugated to ZBP-89, SUMO exerts a strong inhibitory effect on such synergistic interactions through a critical conserved functional surface. By regulating higher order functional interactions, sumoylation provides a reversible post-translational mechanism to control the activity of ZBP-89.
Chupreta
Sergey
S
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA.
Brevig
Holly
H
Bai
Longchuan
L
Merchant
Juanita L
JL
Iñiguez-Lluhí
Jorge A
JA
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D020218:Response Elements / Q000502:physiology*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D020033:Protein Isoforms; D025842:SUMO-1 Protein; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C110951:ZNF148 protein, human