The DSPII splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes.

Desmosomes are intercellular junctions specialised for strong adhesion that are prominent in the epidermis and heart muscle. Defective desmosomal function due to inherited mutations in the constitutive desmosomal gene desmoplakin (DSP) causes skin or heart disorders and in some instances both. Different mutations have different disease-causing molecular mechanisms as evidenced by the varying phenotypes resulting from mutations affecting different domains of the same protein, but the majority of these mechanisms remain to be determined.

Connexins in epidermal homeostasis and skin disease.

The expression of multiple connexin (Cx) types in the epidermis, their differential expression during wound closure and the association of skin pathology with specific Cx gene mutations, are indicative of important functions for Cxs in the skin. In this review, we focus on the role of Cx proteins in the epidermis and during wound healing and discuss mutations in Cx genes which cause skin disease. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

EKV mutant connexin 31 associated cell death is mediated by ER stress.

The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies reveal tissue-specific effects of these Cx31 disease-associated mutations.

Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5.

Retromer is a membrane-associated heteropentameric coat complex that functions in the endosome-to-Golgi retrieval of the cation-independent mannose-6-phosphate receptor, the Wntless protein and other membrane proteins of physiological significance. Retromer comprises two functional subcomplexes: the cargo-selective subcomplex is a trimer of the VPS35, VPS29, VPS26 proteins, whereas the sorting nexin proteins, Snx1 and Snx2 function to tubulate the endosomal membrane. Unlike the sorting nexins, which contain PtdIns3P-binding PX domains, the cargo-selective VPS35/29/26 complex has no lipid-binding domains and its recruitment to the endosomal membrane remains mechanistically uncharacterised.

Premature terminal differentiation and a reduction in specific proteases associated with loss of ABCA12 in Harlequin ichthyosis.

One of the primary functions of skin is to form a defensive barrier against external infections and water loss. Disrupted barrier function underlies the most severe and often lethal form of recessive congenital ichthyosis, harlequin ichthyosis (HI). HI is associated with mutations in the gene that encodes the ABC transporter protein, ABCA12.

EHD1 interacts with retromer to stabilize SNX1 tubules and facilitate endosome-to-Golgi retrieval.

Endosome-to-Golgi retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR) requires the function of the retromer complex. Retromer is localized to endosomes and comprises two distinct sub complexes: the vacuolar protein sorting 35/29/26 sub complex that binds cargo and the sorting nexin (SNX)1/2 sub complex that tubulates endosomal membranes. To identify up- or down-stream regulatory factors of retromer, a comparative proteomic strategy was employed.

Identification of a conserved motif required for Vps35p/Vps26p interaction and assembly of the retromer complex.

The retromer complex is a conserved cytoplasmic coat complex that mediates the endosome-to-Golgi retrieval of vacuole/lysosome hydrolase receptors in yeast and mammals. The recognition of cargo proteins by the retromer is performed by the Vps35p/VPS35 (where Vps is vacuolar protein sorting) component, which together with Vps26p/VPS26 and Vps29p/VPS29, forms the cargo-selective subcomplex. In this report, we have identified a highly-conserved region of Vps35p/VPS35 that is essential for the interaction with Vps26p/VPS26 and for assembly of the retromer complex.

A deafness-associated mutant human connexin 26 improves the epithelial barrier in vitro.

A large proportion of recessive nonsyndromic hearing loss is due to mutations in the GJB2 gene encoding connexin 26 (Cx26), a component of a gap junction. Within different ethnic groups there are specific common recessive mutations, each with a relatively high carrier frequency, suggesting the possibility of heterozygous advantage. Carriers of the R143W GJB2 allele, the most prevalent in the African population, present with a thicker epidermis than noncarriers.