A nonsecretory antimicrobial peptide mediates inflammatory organ damage in Drosophila renal tubules

Ayano Oi; Natsuki Shinoda; Shun Nagashima; Masayuki Miura; Fumiaki Obata

doi:10.1016/j.celrep.2024.115082

A nonsecretory antimicrobial peptide mediates inflammatory organ damage in Drosophila renal tubules

Cell Rep. 2024 Dec 14:115082. doi: 10.1016/j.celrep.2024.115082. Online ahead of print.

Authors

Ayano Oi¹, Natsuki Shinoda², Shun Nagashima³, Masayuki Miura², Fumiaki Obata⁴

Affiliations

¹ Laboratory for Nutritional Biology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan; Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
² Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Laboratory of Regenerative Medicine, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
⁴ Laboratory for Nutritional Biology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan; Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: fumiaki.obata@riken.jp.

PMID: 39719708
DOI: 10.1016/j.celrep.2024.115082

Abstract

An excessive immune response damages organs, yet its molecular mechanism is incompletely understood. Here, we screened a factor mediating organ damage upon genetic activation of the innate immune pathway using Drosophila renal tubules. We found that an antimicrobial peptide, Attacin-D (AttD), causes organ damage upon immune deficiency (Imd) pathway activation in the Malpighian tubules. Loss of AttD function suppresses most of the pathological phenotypes induced by Imd activation, such as cell death, bloating of the whole animal, and mortality, without compromising the immune activation. AttD is required for the immune-induced damage specifically in the Malpighian tubules and not the midgut. Unlike other antimicrobial peptides, AttD lacks a signal peptide and stays inside tubular cells, potentially damaging the tubular cells via aggregation and oligomerization. Suppression of AttD almost completely attenuates the pathology caused by a gut-tumor-induced immune activation. Our study elucidates the mechanistic effector of immune-induced organ damage.

Keywords: Attacin-D; CP: Immunology; CP: Microbiology; Drosophila melanogaster; Imd pathway; Malpighian tubules; antimicrobial peptide; cell death; gut tumor; innate immunity; renal tubules; water homeostasis.