AUTHOR=Cao Lu , Yan Dong , Xiao Jun , Feng Hao , Chang Ming Xian 

TITLE=The Zebrafish Antiapoptotic Protein BIRC2 Promotes Edwardsiella piscicida Infection by Inhibiting Caspases and Accumulating p53 in a p53 Transcription-Dependent and -Independent Manner

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.781680

DOI=10.3389/fimmu.2021.781680

ISSN=1664-3224

ABSTRACT=<p>IAPs (inhibitors of apoptosis) are endogenous caspase inhibitors with multiple biological activities. In the present study, we show functional characteristics of antiapoptotic protein BIRC2 (cIAP1) in response to <italic>Edwardsiella piscicida</italic> infection. Overexpression of BIRC2 in zebrafish larvae promoted the proliferation of <italic>E. piscicida</italic>, leading to a decreased larvae survival. The expression levels of caspases including <italic>casp3</italic>, <italic>casp8</italic>, and <italic>casp9</italic> were significantly inhibited by BIRC2 overexpression in the case of <italic>E. piscicida</italic> infection. Treatment of zebrafish larvae microinjected with BIRC2 with the caspase activator PAC-1 completely blocked the negative regulation of BIRC2 on the <italic>E. piscicida</italic> infection, with the reduced inhibition on the <italic>casp3</italic> and without inhibition on <italic>casp8</italic> and <italic>casp9</italic>. In contrast to the regulation of BIRC2 on the caspases, BIRC2 overexpression significantly induced the expression of p53, especially at 24 hpi. In addition to the cytoplasmic p53 expression, BIRC2 overexpression also induced the expression of the nuclear p53 protein. Further analysis demonstrated that BIRC2 could interact and colocalize with p53 in the cytoplasm. The numbers of <italic>E. piscicida</italic> in larvae overexpressed with BIRC2 and treated with pifithrin-μ (an inhibitor of mitochondrial p53) or pifithrin-α (an inhibitor of p53 transactivation) were lower than those of larvae without pifithrin-μ or pifithrin-α treatment. Critically, the p53 inactivators pifithrin-μ and pifithrin-α had no significant effect on larval survival, but completely rescued larval survival for zebrafish microinjected with BIRC2 in the case of <italic>E. piscicida</italic> infection. Collectively, the present study suggest that piscine BIRC2 is a negative regulator for antibacterial immune response in response to the <italic>E. piscicida</italic> infection <italic>via</italic> inhibiting caspases, and accumulating p53 in a p53 transcription-dependent and -independent manner.</p>