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The Ubiquitin E3 Ligase PUB17 Positively Regulates Immunity by Targeting a Negative Regulator, KH17, for Degradation.

ABSTRACT: Ubiquitination is a post-translational modification that regulates many processes in plants. Several ubiquitin E3 ligases act as either positive or negative regulators of immunity by promoting the degradation of different substrates. StPUB17 is an E3 ligase that has previously been shown to positively regulate immunity to bacteria, fungi and oomycetes, including the late blight pathogen Phytophthora infestans. Silencing of StPUB17 promotes pathogen colonization and attenuates Cf4/avr4 cell death. Using yeast-2-hybrid and co-immunoprecipitation we identified the putative K-homology (KH) RNA-binding protein (RBP), StKH17, as a candidate substrate for degradation by StPUB17. StKH17 acts as a negative regulator of immunity that promotes P. infestans infection and suppresses specific immune pathways. A KH RBP domain mutant of StKH17 (StKH17^GDDG) is no longer able to negatively regulate immunity, indicating that RNA binding is likely required for StKH17 function. As StPUB17 is a known target of the ubiquitin E3 ligase, StPOB1, we reveal an additional step in an E3 ligase regulatory cascade that controls plant defense.

SUBMITTER: McLellan H

PROVIDER: S-EPMC7371183 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CCAAT/enhancer-binding protein alpha (C/EBP?) is an important transcription factor involved in granulocytic differentiation. Here, for the first time we demonstrate that E6-associated protein (E6AP), an E3 ubiquitin ligase targets C/EBP? for ubiquitin-mediated proteasome degradation and thereby negatively modulates its functions. Wild-type E6AP promotes ubiquitin dependent proteasome degradation of C/EBP?, while catalytically inactive E6-associated protein having cysteine replaced with alanine at amino-acid position 843 (E6AP-C843A) rather stabilizes it. Further, these two proteins physically associate both in non-myeloid (overexpressed human embryonic kidney epithelium) and myeloid cells. We show that E6AP-mediated degradation of C/EBP? protein expression curtails its transactivation potential on its target genes. Noticeably, E6AP degrades both wild-type 42?kDa CCAAT-enhancer-binding protein alpha (p42C/EBP?) and mutant isoform 30?kDa CCAAT-enhancer-binding protein alpha (p30C/EBP?), this may explain perturbed p42C/EBP?/p30C/EBP? ratio often observed in acute myeloid leukemia (AML). We show that overexpression of catalytically inactive E6AP-C843A in C/EBP? inducible K562- p42C/EBP?-estrogen receptor (ER) cells inhibits ?-estradiol (E2)-induced C/EBP? degradation leading to enhanced granulocytic differentiation. This enhanced granulocytic differentiation upon E2-induced activation of C/EBP? in C/EBP? stably transfected cells (?-estradiol inducible K562 cells stably expressing p42C/EBP?-ER (K562-C/EBP?-p42-ER)) was further substantiated by siE6AP-mediated knockdown of E6AP in both K562-C/EBP?-p42-ER and 32dcl3 (32D clone 3, a cell line widely used model for in vitro study of hematopoietic cell proliferation, differentiation, and apoptosis) cells. Taken together, our data suggest that E6AP targeted C/EBP? protein degradation may provide a possible explanation for both loss of expression and/or functional inactivation of C/EBP? often experienced in myeloid leukemia.

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The Ubiquitin E3 Ligase PUB17 Positively Regulates Immunity by Targeting a Negative Regulator, KH17, for Degradation.

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