RUFY4 exists as two translationally regulated isoforms, that localize to the mitochondrion in activated macrophages.

Jan Valečka,Catarina R Almeida,Philippe Pierre,Seigo Terawaki,Voahirana Camosseto,Bing Su,Zhuangzhuang Liu,Ivan Dikic,David G Mcewan,Yinming Liang,Eva Strock,Evelina Gatti

doi:10.1098/rsos.202333

Abstract

We report here that RUFY4, a newly characterized member of the ‘RUN and FYVE domain-containing’ family of proteins previously associated with autophagy enhancement, is highly expressed in alveolar macrophages (AM). We show that RUFY4 interacts with mitochondria upon stimulation by microbial-associated molecular patterns of AM and dendritic cells. RUFY4 interaction with mitochondria and other organelles is dependent on a previously uncharacterized OmpH domain located immediately upstream of its C-terminal FYVE domain. Further, we demonstrate that rufy4 messenger RNA can be translated from an alternative translation initiation codon, giving rise to a N-terminally truncated form of the molecule lacking most of its RUN domain and with enhanced potential for its interaction with mitochondria. Our observations point towards a role of RUFY4 in selective mitochondria clearance in activated phagocytes.

Highlights

The RUN and FYVE domain-containing proteins (RUFY) family encompass five conserved genes displaying tissue-specific expression [1]
microbe-associated molecular patterns (MAMPs) triggering of Toll-likereceptor 4 (TLR4), as well as interferons or IL-1ß exposure promotes phagocytes activation resulting in secretion of inflammatory cytokines and enhanced antigen processing and presentation
It is expected that molecules like RUFY4 that have a pattern of expression restricted to immune cells and play a regulatory role in different aspects of membrane traffic, would be functionally regulated upon dendritic cells (DCs) or macrophages activation by MAMPs like LPS

Summary

Introduction

The RUN and FYVE domain-containing proteins (RUFY) family encompass five conserved genes displaying tissue-specific expression [1]. RUFY family protein dysfunction, can lead to severe pathologies, including cancer [1]. They share a common structural organization with an N-terminal RUN domain, several coiled-coil (CC) motifs and a PtdIns(3)P-interacting C-terminal FYVE domain. RUFY4 can interact with phosphatidylinositol 3-phosphate (PtdIns(3)P)-enriched membranes [3] and upon overexpression, induce the degradation of the autophagy effector LC3/ATG8 together with the perinuclear clustering of late endosomal compartments and autophagosomes [4]. By optimizing effector proteins activity and organelles distribution, RUFY4 expression facilitates the elimination of intracellular bacteria like Brucella abortus, and Salmonella typhimurium replication [4,7], suggesting that it has a role in the cell response to bacterial infection

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