Abstract
ABSTRACTMouse Apolipoprotein L9 is a 34-kDa phosphatidylethanolamine (PE)-binding protein. The gene is present only in mouse and rat genomes; hence it is restricted to two species. To understand why, it is essential to uncover details about its functions in cellular processes. Here we show that ApoL9 interacts with the proteins of the LC3 and GABARAP subfamilies, which are key players in macroautophagy. In vitro binding studies show a strong association with GABARAP, and in amino acid-starved cells it preferentially interacts with lipidated LC3B, likely by binding to its PE moiety through its lipid-binding domain. On treatment with autophagy inhibitors bafilomycin A1 and chloroquine, ApoL9 is found near swollen mitochondria and on lysosomes/LAMP1-positive compartments. However, ApoL9 itself does not seem to be degraded as a result of autophagy, suggesting that it is not an autophagy cargo receptor. Deletions in a putative transmembrane region between amino acids 110 and 145 abolish binding to PE. In addition, ApoL9 can redistribute to stress granules, can homo-oligomerize, and is a microtubule-associated protein. In short, its distribution in the cell is quite widespread, suggesting that it could have functions at the intersection of membrane binding and reorganization, autophagy, cellular stress and intracellular lipid transport.This article has an associated First Person interview with the first author of the paper.
Highlights
Mouse ApoL9, encoded by two independent genes Apol9a and Apol9b on chromosome 15, has previously been shown to have either antiviral or pro-viral effects during infection of cells by different types of viruses (Kreit et al, 2014, 2015; Arvind and Rangarajan, 2016)
ApoL9 interacts with the mammalian orthologues of Atg8 We previously reported that ApoL9 localizes to ALIS-like structures, which contain LC3 and SQSTM1, proteins that have key roles in autophagic processes (Arvind and Rangarajan, 2016)
SDS-PAGE followed by immunoblotting with anti-V5 antibody revealed that ApoL9 interacts with all the members of the LC3 and GABARAP subfamilies, and that the interaction was strongest with GABARAP and GABARAPL1 (Fig. 1A)
Summary
Mouse ApoL9, encoded by two independent genes Apol9a and Apol9b on chromosome 15, has previously been shown to have either antiviral or pro-viral effects during infection of cells by different types of viruses (Kreit et al, 2014, 2015; Arvind and Rangarajan, 2016). Expression of ApoL proteins is induced by interferons and TNF-α (Zhaorigetu et al, 2011; Monajemi et al, 2002). Small quantities of ApoL9 secreted from macrophages during interferon induction have been shown to promote epithelial. We used B16F10 melanoma cells to look at the basic expression pattern of constructs expressing ApoL9, examined its levels in various mouse tissues, and viewed it in the context of infection by Japanese Encephalitis virus (Arvind and Rangarajan, 2016). ApoL9 is expressed at moderate-to-high levels in mouse liver and brain, suggesting some function of relevance for the protein in these major tissues
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