Roles of VPS33B and VIPAR in epidermal homeostasis

Mutations in VPS33B and VIPAS39 cause the rare multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis(ARC) syndrome. The encoded VPS33B and VIPAR proteins interact and act as part of an as yet only partly characterized tethering complex; the class C Homologues in Endosome-Vesicle Interaction (CHEVI) complex. Severe ichthyosis is also ever present in ARC syndrome patients but is currently understudied. Previous studies showed entombed lamellar body-like structures in the cornified skin layer; however the molecular mechanisms underlying this ichthyosis and the specific role of the CHEVI complex in the epidermis are yet to be defined. VPS33B and VIPAR were recently shown to be required for the delivery of lysyl hydroxylase 3 (LH3), a collagen-modifying enzyme, to intracellular collagen. Co-immunoprecipitation analysis demonstrated interactions with Rab10 and Rab25 GTPases, whose activity is required for LH3 delivery. This allowed confirmation that a novel VPS33B variant was pathogenic in patients with a mild ARC-like phenotype, as this variant disrupted VPS33B interactions with Rab GTPases. The variant also disrupted LH3 delivery and patient skin biopsies showed parallel phenotypes to VPS33B-deficient mice further confirming that this variant is pathogenic for this novel syndrome. Inducible Vps33b and Vipar (Vipas39) ubiquitous knockout murine models develop a skin phenotype similar to ARC patients with analysis of skin biopsies showing defects in epidermal differentiation. Trans-epidermal water loss measurements indicated defective barrier function. A reduction in epidermal lipids was identified in the epidermis of these mice and abnormalities in lamellar bodies that secrete these lipid layers were identified, suggesting disrupted lipid delivery is causing the defective barrier function. My findings suggest VPS33B-VIPAR are important for epidermal delivery of lipids and/or lamellar bodies in addition to their role in LH3 delivery. VPS33B or VIPAR deficiency leads to defects in lipid and LH3 delivery, producing defects in keratinocyte differentiation and the epidermal barrier