Regulation of immature protein dynamics in the endoplasmic reticulum.

The quality of nascent protein folding in vivo is influenced by the microdynamics of the proteins. Excessive collisions between proteins may lead to terminal misfolding, and the frequency of protein interactions with molecular chaperones determines their folding rates. However, it is unclear how immature protein dynamics are regulated. In this study, we analyzed the diffusion of immature tyrosinase in the endoplasmic reticulum (ER) of non-pigmented cells by taking advantage of the thermal sensitivity of the tyrosinase. The diffusion of tyrosinase tagged with yellow fluorescence protein (YFP) in living cells was directly measured using fluorescent correlation spectroscopy. The diffusion of folded tyrosinase in the ER of cells treated with brefeldin A, as measured by fluorescent correlation spectroscopy, was critically affected by the expression level of tyrosinase-YFP. Under defined conditions in which random diffusional motion of folded protein was allowed, we found that the millisecond-order diffusion rate observed for folded tyrosinase almost disappeared for the misfolded molecules synthesized at a nonpermissive high temperature. This was not because of enhanced aggregation at the high temperature, as terminally misfolded tyrosinase synthesized in the absence of calnexin interactions showed comparable, albeit slightly slower, diffusion. Yet, the thermally misfolded tyrosinase was not immobilized when measured by fluorescence recovery after photobleaching. In contrast, terminally misfolded tyrosinase synthesized in cells in which alpha-glucosidases were inhibited showed extensive immobilization. Hence, we suggest that the ER represses random fluctuations of immature tyrosinase molecules while preventing their immobilization.

Apoeccrine sweat duct obstruction as a cause for Fox-Fordyce disease.

The pathogenesis of Fox-Fordyce disease has been reported to be hyperkeratosis and obstruction of the upper hair follicle, where the duct of the apocrine sweat gland opens. We report a case of Fox-Fordyce disease with full clinical manifestation. It appeared to be caused by the obstruction of intraepidermal apoeccrine sweat ducts by apoeccrine secretory cells detached and released from the secretory epithelium. A 24-year-old woman visited our clinic with intensely pruritic papules on axillae, mammary areolae, and pubic areas. Histopathologic examination revealed an obstruction of the sweat duct in the epidermis, which opened directly to the skin surface. The closing substance of the duct was an aggregate of epithelial cells, probably derived from the secretory portion. In the dermis, the secretory cells of apocrinelike sweat glands had been detaching from the secretory epithelia. These findings suggest that Fox-Fordyce disease can occur by the mechanism in which apoeccrine secretory cells obstruct sweat ducts.