VPS33B gene

The VPS33B gene (VPS33B stands for Vacuolar Protein Sorting-Associated Protein 33B) is a protein-coding gene located on chromosome 15q26.1. An important paralog of this gene is VPS33A. Alternative splicing leads to several transcript variants.

Vesicle-mediated protein sorting plays an important role in the separation of intracellular molecules into different organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting genes (VPS genes) involved in the transport of vesicles to vacuoles. This gene belongs to the Sec-1 domain family and encodes the human ortholog of the rat gene Vps33b, which is homologous to the yeast class C protein Vps33. Mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes and, like their yeast counterparts, may mediate vesicle transport steps in the endosome/lysosome signaling pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome.

The encoded protein may play a role in vesicle-mediated protein transport to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. It is required for the proper transport and targeting of the collagen-modifying enzyme lysylhydroxylase 3 (LH3) to intracellular collagen (Gruber R et al. 2017)

Mediates phagolysosome fusion in macrophages (PubMed:18474358). Presumably involved in endosome maturation with the participation of VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of apical-basolateral polarity (Bach H et al. 2008). Appears to be involved in sorting specific cargoes from the trans-Golgi network to alpha-granular multivesicular bodies (MVBs), thereby promoting MVBs maturation in megakaryocytes.

Diseases associated with VPS33B include

• Arthrogryposis, renal dysfunction and cholestasis
• Progressive familial intrahepatic cholestasis, 12.
• ARKID syndrome (biallelic mutations in VPS33B)

1. Alter S et al. (2018) Novel VPS33B mutation in a patient with autosomal recessive keratoderma-ichthyosis-deafness syndrome. Am J Med Genet A 176:2862-2866
2. Bach H et al. (2008) Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell Host Microbe. 2008 May 15;3(5):316-22.
3. Gruber R et al. (2017) Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification. J Invest Dermatol 137:845-854.