Drosophila Cul3 contributes to Diap2-mediated innate immune signaling for antimicrobial defense
Fanrui Kong,
Zixuan Wang,
Chuchu Zhang,
Yihua Xiao,
Muhammad Abdul Rehman Saeed,
Weini Li,
Akira Goto,
Qingshuang Cai,
Shanming Ji
Affiliations
Fanrui Kong
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China
Zixuan Wang
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China
Chuchu Zhang
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China
Yihua Xiao
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China
Muhammad Abdul Rehman Saeed
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China
Weini Li
Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, California, USA
Akira Goto
INSERM, Université de Strasbourg, CNRS, Insect Models of Innate Immunity (M3I; UPR9022), Bas-Rhin, France
Qingshuang Cai
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Bas-Rhin, France; Correspondence:
Shanming Ji
Center for Developmental Biology, School of Life Sciences, Anhui Agricultural University, Anhui, China; Correspondence:
The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections. Herein, we investigate the functional role of Cullin-3 (Cul3), one critical constituent of Cullin-RING ubiquitin ligases, in the Drosophila melanogaster (fruit fly) antimicrobial immune defense. We show that silencing of Cul3 leads to a decreased induction of antimicrobial peptides and high mortality in adult flies after bacterial infection. Through biochemical approaches, we demonstrate that Cul3 predominantly relies on its BTB-binding domain and neddylation domain to physically associate with death-associated inhibitor of apoptosis 2 (Diap2). Importantly, Cul3 ameliorates the Diap2-mediated ubiquitination of death-related ced-3/Nedd2-like caspase (Dredd), a process essential for robust immune deficiency signaling upon bacterial infection. Taken together, our findings highlight a previously unrecognized regulatory axis of Cul3/Diap2/Dredd in the fly antimicrobial immune defense, providing potential insights into therapeutic strategies for combating bacterial infections in humans.
