ATG14 and STX18: gatekeepers of lipid droplet degradation and the implications for disease modulation.

Lipophagy, a form of autophagy specific to the degradation of lipid droplets (LDs), plays an important role in the maintenance of cellular homeostasis and metabolic processes. A recent study has identified ATG14 (autophagy related 14) as a molecule that targets LDs and marks them for degradation via lipophagy; a process that is inhibited by the binding of STX18 (syntaxin 18) to ATG14 in mammalian cells. The exact mechanism of regulation of lipophagy, and subsequently of cellular LD levels, is still under investigation; however, dysregulation of this process has been linked to a number of disease phenotypes. An imbalance of lipid levels can result in a wide variety of conditions depending on the cell/tissue type in which they occur. In cells of the retinal pigment epithelium, lipid accumulation can result in dry age-related macular degeneration, in hepatocytes it can result in nonalcoholic fatty liver diseases and in neural cells it can result in the pathogenesis of neurodegenerative conditions such as Alzheimer and Parkinson diseases. Based upon its wide range of implications in diseases, modulation of lipophagy is currently being further investigated for its potential as a treatment for a variety of conditions ranging from viral infection to developmental illnesses.

Coronavirus hijacks STX18-ATG14 axis-regulated lipophagy to evade an anti-viral effect.

ATG14 is a core subunit of the class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) for macroautophagy/autophagy initiation and also binds to the STX17 to promote autophagosome-lysosome fusion. Our recent work found that ATG14 also targets lipid droplets (LDs) and interacts with mammalian Atg8-family proteins (ATG8s) to mediate lipophagy (selective autophagic degradation of lipid droplets). We also demonstrated that STX18 (syntaxin 18) acts as a negative regulator that disrupts the interactions of ATG14-ATG8s and the formation of the PtdIns3K-C1 through binding to ATG14. Furthermore, we found that knockdown of STX18 induces LD-associated anti-viral protein RSAD2/Viperin degradation dependent on ATG14-mediated lipophagy. Additionally, coronavirus M protein hijacks STX18 to induce lipophagy and degrade RSAD2, facilitating virus production. In summary, our findings reveal new roles of ATG14 in lipid metabolism and viral replication as an autophagic receptor.

Characterization of soluble N-ethylmaleimide-sensitive factor attachment protein receptor gene STX18 variations for possible roles in congenital heart diseases.

Congenital heart disease (CHD) is among the most prevalent and complex congenital anatomic malformations in newborns. Interactions of cardiac progenitor with a broad range of cellular regulatory factors play key roles in the formation of mammalian heart and pathogenesis of CHD. STX18 is a soluble N-ethylmaleimide-sensitive factor attachment protein receptor, which is involved in numeral cellular activities such as organelle assembly and the cell cycle. The aim of this work was to find evidence on whether STX18 variations might be associated with CHD in Chinese Han populations. We evaluated SNPs rs2044, rs33952588, rs61740788, rs12504020 and rs12644497, which are located within the exon or intron sequences of the STX18 gene, for 310 Chinese Han CHD patients and 400 non-CHD controls. Using SPSS software (version 19.0) and the online software OEGE, we conducted statistical analyses and Hardy-Weinberg equilibrium test, respectively. Among the five SNPs identified in the STX18 gene, rs33952588 and rs61740788 had very low genetic heterozygosity. In contrast, the genetic heterozygosity of the remaining three variations rs12504020 and rs12644497 near the 5'UTR and rs2044 within 3'UTR of the STX18 gene was considerably high. Analysis of associations of these genetic variations with the risk of CHD showed that rs12644497 (P value=0.017<0.05) was associated with the risk of CHD, specifically VSD and ASD, whereas rs12504020 (P value=0.560>0.05) and rs2044 (P value=0.972>0.05) were not. The SNP rs12644497 in the STX18 gene was associated with CHD in Chinese Han populations.