Background: Pendred syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4 +/+ or Slc26a4 +/-) or lack (Slc26a4 -/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4 -/-mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration.
As a member of the tetraspanin superfamily of proteins, CD81 has been linked to a number of biologic functions including cellular proliferation, differentiation, activation, and degranulation. As a co-receptor for hepatitis C virus, and a requirement for hepatocytes for infectivity of human Plasmodium falciparum and rodent P. yoelii sporozoite infectivity, CD81 may also play a vital role in pathology. Despite the importance of CD81 in multiple cellular functions, the molecular mechanism of action of CD81 in these processes has remained elusive. Here we report an association between CD81 and the epsilon isoform of 14-3-3, a serine/threonine-binding intracellular signaling protein. Furthermore, we provide evidence that in human, this association is influenced by the palmitoylation state of the CD81 cytoplasmic tails. We have generated a series of CD81 cysteine mutants to identify palmitoylated intracellular motifs of CD81, and reveal palmitoylation on the N-and C-terminal tails as well as the intracellular loop between transmembrane domains 2 and 3. One of these mutants lacks all five of its intracellular cysteines and therefore cannot be palmitoylated. This unpalmitoylated version of CD81 shows constitutive association with 14-3-3. Interestingly, we find that under oxidative conditions, CD81 palmitoylation is inhibited and that condition correlates with the association of CD81 and 14-3-3. These finding suggest that CD81 signaling events could be mediated by 14-3-3 adapter proteins, and these signals may be dependent on cellular redox.CD81 is a member of the tetraspanin family of integral membrane proteins. CD81 was first discovered in 1990 as the target of an antibody with reversible antiproliferative effects on a human B cell lymphoma line (1-4). There are currently 26 membrane proteins classified as members of the tetraspanin family. Members must meet the following criteria: four highly conserved hydrophobic transmembrane domains, two extracellular loops, short intracellular amino and carboxyl tails, and three motifs, CCG, PXSC, and EGC, that contain conserved cysteine residues in the major extracellular domain (5). The smaller extracellular loop is between transmembrane 1 and 2, and the larger extracellular loop, which is likely to mediate interactions with other cell surface proteins, lies between transmembrane 3 and 4.Many of the initial discoveries of CD81 function were focused in the immune system. On the surface of B cells, CD81 is associated with the CD19⅐CD21⅐Leu 13 protein complex (6 -8). This complex is involved in regulation of B cell receptor signal transduction through recruitment of phosphatidylinositol 3-kinase (PI3K). The CD21⅐CD19⅐CD81 complex functions by bringing together required signaling molecules to lower the B cell threshold of activation (9, 10). Similarly, on T cells, CD81 associates with the T cell co-receptors CD4 and CD8 and provides a costimulatory signal with the CD3 subunit of the T cell receptor (11). CD81 may play a role in early T cell development in the thymus (12). The roles...
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