Keratins Stabilize Hemidesmosomes through Regulation of β4-Integrin Turnover
Keratins Stabilize Hemidesmosomes through Regulation of β4-Integrin Turnover
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DOI：
10.1038/jid.2015.46
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发表时间：
2015-06-01
影响因子：
6.5
通讯作者：
Magin, Thomas M.
中科院分区：
文献类型：
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作者：
Seltmann, Kristin;Cheng, Fang;Magin, Thomas M.
表皮完整性和伤口愈合依赖于包括半脂质体在内的细胞-基质接触的重塑。β 4-整合素和粘附素的突变可导致严重的大疱性表皮松解症（EB）。引起EB单纯性的角蛋白K5或K14的突变是否也通过改变半粒染色体成分而损害细胞-基质粘附尚未得到很好的研究。特别是，β 4-整合素内吞作用和转换对角蛋白的依赖性仍未完全了解。在这里，我们发现角蛋白的缺失导致凝集素- β 4-整合素相互作用的丧失和β 4-整合素Ser1354和Ser1362位点磷酸化的升高。这触发了角化细胞中β 4-整合素依赖的内吞作用，但没有通过Rab5和Rab11室引起其他整合素的内吞作用。表达缺乏磷酸化的β 4-整合素突变体可减少β 4-整合素的内吞作用，并挽救无角蛋白细胞中的plectin定位。在没有角蛋白的情况下，β 4-整合素的磷酸化是由于EGFR和PKC α信号通路下游Erk1/2活性升高引起的。此外，Erk1/2磷酸化增加和粘连蛋白定位改变发生在角蛋白缺乏的小鼠表皮中。引人注目的是，K14-R125P EBS突变体的表达也导致粘附素错定位和β 4整合素周转升高，这表明与疾病有关。我们的数据强调了角蛋白在控制β 4-整合素内吞作用中的主要作用，涉及与表皮分化和发病相关的凝集素- erk1 /2依赖机制。
Epidermal integrity and wound healing depend on remodeling of cell-matrix contacts including hemidesmosomes. Mutations in beta 4-integrin and plectin lead to severe epidermolysis bullosa (EB). Whether mutations in keratins K5 or K14, which cause EB simplex, also compromise cell-matrix adhesion through altering hemidesmosomal components is not well investigated. In particular, the dependence of beta 4-integrin endocytosis and turnover on keratins remains incompletely understood. Here, we show that the absence of keratins causes loss of plectin-beta 4-integrin interaction and elevated beta 4-integrin phosphorylation at Ser1354 and Ser1362. This triggered a caveolin-dependent endocytosis of beta 4-integrin but not of other integrins through Rab5 and Rab11 compartments in keratinocytes. Expressing a phospho-deficient beta 4-integrin mutant reduces beta 4-integrin endocytosis and rescues plectin localization in keratin-free cells. beta 4-integrin phosphorylation in the absence of keratins resulted from elevated Erk1/2 activity downstream of increased EGFR and PKC alpha signaling. Further, increased Erk1/2 phosphorylation and altered plectin localization occur in keratin-deficient mouse epidermis in vivo. Strikingly, expression of the K14-R125P EBS mutant also resulted in plectin mislocalization and elevated beta 4-integrin turnover, suggesting disease relevance. Our data underscore a major role of keratins in controlling beta 4-integrin endocytosis involving a plectin-Erk1/2-dependent mechanism relevant for epidermal differentiation and pathogenesis.