This entry represents a domain found in the vacuolar sorting protein Vps39 and transforming growth factor beta receptor-associated protein Trap1. Vps39, a component of the C-Vps complex, is thought to be required for the fusion of endosomes and other types of transport intermediates with the vacuole [, ]. In Saccharomyces cerevisiae (Baker's yeast), Vps39 has been shown to stimulate nucleotide exchange []. Trap1 plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling [, ]. The precise function of this domain has not been characterised In Vps39 this domain is involved in localisation and in mediating the interactions with Vps11 [].
This entry represents a domain found in the vacuolar sorting protein Vps39 and transforming growth factor beta receptor-associated protein Trap1. Vps39, a component of the C-Vps complex, is thought to be required for the fusion of endosomes and other types of transport intermediates with the vacuole [, ]. In Saccharomyces cerevisiae (Baker's yeast), Vps39 has been shown to stimulate nucleotide exchange []. Trap1 plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling [, ]. The precise function of this domain has not been characterised.
This entry includes fungal Vam6/Vps3 and animal Vps39/TRAP1. Vps39 is also known as Vam6 or TRAP1-Like-Protein (TLP) []. Vam6/Vps39 acts as a component of the HOPS complex that functions during the docking stage of vacuole fusion. It is required for late endosomal-lysosomal fusion events and the delivery of endocytic cargo to lysosomes [, ]. In addition to its regulatory role in homotypic vacuolar fusion and vacuole protein sorting within the HOPS complex, Vam6 also controls the function of the central regulator of eukaryotic cell growth TORC1 by activating the Gtr1 subunit of the EGO complex [, ].TRAP1 plays a role in vesicle-mediated protein trafficking of the endocytic membrane transport pathway [].
Coronavirus encodes two viroporins, E protein and protein 3a, which act as ion-conductive pores in planar lipid bilayers and are required for maximal SARS-CoV replication and virulence []. In betacoronavirus, this protein plays a role in viral egress via lysosomal trafficking [, ]. Protein 3a from SARS-CoV-2 also blocks autolysosomes formation by binding and sequestering the host component VPS39 for homotypic fusion and protein sorting (HOPS) on late endosomes. This prevents fusion of autophagosomes with lysosomes, disrupting autophagy and facilitating virus egress [].This entry represents protein 3a encoded by Orf3/3a, also known as X1, which forms homotetrameric potassium, sodium or calcium sensitive ion channels (viroporin) and may modulate virus release. It has also been shown to up-regulate expression of fibrinogen subunits FGA, FGBand FGG in host lung epithelial cells [, , , ].3a protein is a pro-apoptosis-inducing protein. It localises to the endoplasmic reticulum (ER)-Golgi compartment. SARS-CoV causes apoptosis of infected cells through NLRP3 inflammasome activation, as ORF3a is a potent activator of the signals required for this activation, pro-IL-1beta gene transcription and protein maturation. This protein also promotes the ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediated by its interaction with TNF receptor-associated factor 3 (TRAF3). The expression of ORF3a induces NF-kappa B activation and up-regulates fibrinogen secretion with the consequent high cytokine production [, , , ]. Another apoptosis mechanism described for this protein is the activation of the PERK pathway of unfolded protein response (UPR), which causes phosphorylation of eIF2alpha and leads to reduced translation of cellular proteins as well as the activation of pro-apoptotic downstream effectors (i.e ATF4, CHOP) [].
