Abstract
STX19 is an unusual Qa-SNARE as it lacks a C-terminal transmembrane domain. However, it is efficiently targeted to post-Golgi membranes. Here, we set out to determine the intracellular localisation of endogenous STX19 and elucidate the mechanism by which it is targeted to membranes. We have found that a pool of STX19 is localised to tubular recycling endosomes where it colocalises with MICAL-L1 and Rab8 (which has Rab8a and Rab8b forms). Using a combination of genetic, biochemical and cell-based approaches, we have identified that STX19 is S-acylated at its C-terminus and is a substrate for several Golgi-localised S-acyltransferases, suggesting that STX19 is initially S-acylated at the Golgi before trafficking to the plasma membrane and endosomes. Surprisingly, we have found that S-acylation is a key determinant in targeting STX19 to tubular recycling endosomes, suggesting that S-acylation may play a general role in directing proteins to this compartment. In addition, S-acylation also protects STX19 from proteosomal degradation, indicating that S-acylation regulates the function of STX19 at multiple levels.This article has an associated First Person interview with the first author of the paper.
Highlights
Over the past 30 years, the majority of the molecular machinery required for intracellular protein transport has been identified and functionally characterised
We have set out to determine the intracellular localisation of endogenous syntaxin 19 (STX19) and elucidate the mechanism by which it is targeted to membranes
We have found that a pool of STX19 is localised to tubular recycling endosomes where it co-localises with MICAL-L1 and Rab8
Summary
Over the past 30 years, the majority of the molecular machinery required for intracellular protein transport has been identified and functionally characterised. Our understanding of how this machinery is regulated by post-translational modifications is less clear. This is especially true for lipid-based modifications which are generally more difficult to study. For the majority of these proteins, it is unclear what role S-acylation plays in regulating their function. S-acylation is a reversible post-translational modification of free cysteine residues with fatty acids, predominantly palmitic acid (Smotrys and Linder, 2004); the process is referred to as palmitoylation. Other fatty acids with different chain lengths and unsaturation can be added to S-acylated proteins (Muszbek et al, 1999). S-acylation targets peripheral proteins to membranes and regulates protein trafficking, turnover and cell signalling (Akimzhanov and Boehning, 2015; Linder and Deschenes, 2007; Misaki et al, 2010; Schmick et al, 2014)
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