A straight link is perceived with the susceptibility of such patients to SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) infection, the severity of illness, and the related difficulty in treatment. At the organism level, plasmalogen deficiency is associated with cardiometabolic disorders including obesity and type 2 diabetes in humans. These lipid species display a propensity for non-lamellar phase formation, facilitating membrane fusion, and modulate the activity of membrane-bound proteins such as enzymes and receptors.

In this context, the role of bioactive plasmalogens (vinyl ether glycerophospholipids) is not completely understood. The fact that coronavirus infection provokes the formation of cubic membranes (CM) (denoted also as convoluted membranes) in host cells has not been rationalized in the development of antiviral therapies yet. These results provide evidence for a common role of TMED3 and related TMEDs in the ER stress‐associated, Golgi‐independent secretion of transmembrane proteins.Ĭoronaviruses have lipid envelopes required for their activity. In contrast, TMED2/3/9/10 silencing reduces SARS‐CoV‐2 viral release.

Co‐expression of all four TMEDs improves, while each single expression reduces, the UPS and ion transport function of trafficking‐deficient ΔF508‐CFTR and p.H723R‐pendrin, which cause cystic fibrosis and Pendred syndrome, respectively. Subsequent mechanistic analyses indicate that TMED3 recognizes the ER core‐glycosylated protein cargos and that the heteromeric TMED2/3/9/10 complex mediates their UPS. The gene silencing results reveal that TMED2, TMED3, TMED9 and TMED10 are involved in the UPS of transmembrane proteins, such as CFTR, pendrin and SARS‐CoV‐2 Spike.

Here, this study reports that TMED proteins play a critical role in the ER stress‐associated UPS of transmembrane proteins. However, the targeting mechanisms of membrane proteins for UPS are unknown. Under ER stress conditions, the ER form of transmembrane proteins can reach the plasma membrane via a Golgi‐independent unconventional protein secretion (UPS) pathway. Thus, SARS-CoV-2 may utilize MAM as a viral assembly site, suggesting novel anti-viral treatment strategies for blocking viral replication in host cells. MAM formation and secreted proteome profiles were largely affected by ORF3a expression. RNF5 expression was correlated to ORF3a ubiquitination. Through mass spectrometric identification of the biotinylated lysine residue (K+226 Da) on the viral proteins using Spot-TurboID workflow, 117 and 191 proteins were robustly determined as ORF3a and M interactomes, respectively, and many, including RNF5 (E3 ubiquitin ligase), overlap with the mitochondrial-associated membrane (MAM) proteome. We introduced a 'plug and playable' proximity labeling tool (TurboID-GBP) for interactome mapping of GFP-tagged SARS-CoV-2 ORF3a and M proteins. SARS-CoV-2 ORF3a and membrane (M) protein expression affects ER-derived structures including cubic membrane and double membrane vesicles in coronavirus-infected cells however, the molecular mechanisms underlying ER remodeling remain unclear. The endomembrane reticulum (ER) is largely reorganized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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