Palmitoylation regulates epidermal homeostasis and hair follicle differentiation.
Palmitoylation regulates epidermal homeostasis and hair follicle differentiation.
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DOI：
10.1371/journal.pgen.1000748
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发表时间：
2009-11
期刊：
影响因子：
4.5
通讯作者：
Jackson IJ
中科院分区：
文献类型：
--
作者：
Mill P;Lee AW;Fukata Y;Tsutsumi R;Fukata M;Keighren M;Porter RM;McKie L;Smyth I;Jackson IJ
棕榈酰化是由含有DHHC的棕榈酰酰基转移酶（PAT）家族介导的关键翻译后修饰。与其他脂质修饰不同，棕榈酰化是可逆的，因此通常调节动态蛋白质相互作用。我们发现，小鼠脱毛突变体，脱毛，（dep）是由于一个单一的氨基酸缺失的PAT，Zdhhc 21，导致蛋白质的错误定位和棕榈酰化活性的损失。我们检测了Zdhhc 21蛋白在皮肤中的表达，发现它仅限于特定的毛发谱系。Zdhhc 21功能的丧失导致在基因表达位点处的延迟的毛干分化，而且还导致远离表达位点的毛囊间表皮（IFE）和皮脂腺的增生。毛囊分化的特异性延迟与生长期增殖减弱相关，并通过毛干祖细胞中Lef 1、核β-连环蛋白和Foxn 1水平的降低来反映。在突变型IFE的增厚基底室中，磷酸化ERK和细胞增殖增加，表明通过EGFR或整合素相关受体的信号传导增加，同时关键分化因子Gata 3的表达减少。我们发现，Src家族激酶，Fyn，参与角质形成细胞分化，是Zdhhc 21的直接棕榈酰化的目标，是错误定位在突变卵泡。这项研究是第一个证明棕榈酰化在调节哺乳动物组织稳态发育信号中的关键作用。在胚胎发育过程中，生长和模式在许多水平上受到调节。在基因表达的位置和时间，介导转录活性的信号是主要的调控水平。然而，发育信号可以通过经由翻译后修饰调节蛋白质稳定性、定位和活性来进一步微调。一种这样的修饰是将脂肪酸棕榈酸酯可逆地添加到蛋白质中。这种修饰介导靶蛋白向细胞特定亚结构域的动态运输。一个大家族的酶进行这种棕榈酰化过程，其中每个家族成员对特定目标具有特异性。然而，棕榈酰化在哺乳动物发育过程中的功能意义尚不清楚。我们目前的证据棕榈酰化在小鼠发育过程中的一个关键作用，使用一种特定的棕榈酰化酶的突变，其功能的丧失导致脱毛（dep）小鼠的脱发和皮肤缺损。尽管它在毛囊中的表达受到限制，但这种酶的功能丧失会导致附近结构的发育缺陷。我们发现棕榈酰化在毛发生长和表皮稳态中起着重要的调节作用。
Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear β-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis. During embryonic development, growth and patterning are regulated at many levels. Signals that mediate transcriptional activity, where and when genes are expressed, are a primary level of regulation. However, developmental signals can be further fine-tuned by modulating protein stability, localization, and activity via post-translational modifications. One such modification is the reversible addition of the fatty acid palmitate to proteins. This modification mediates dynamic trafficking of target proteins to specific subdomains of the cell. A large family of enzymes carries out this palmitoylation process, where each family member has specificity towards particular targets. However, the functional significance of palmitoylation during mammalian development is unclear. We present evidence of a critical role for palmitoylation during mouse development using a mutation of a specific palmitoylating enzyme, whose loss of function leads to hair loss and skin defects in depilated (dep) mice. Despite its restricted expression in hair follicles, loss of function of this enzyme results in developmental defects in nearby structures. We show that palmitoylation plays an important regulatory role in hair growth and epidermal homeostasis.
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影响因子：
16
作者：
Cabodi, S;Calautti, E;Dotto, GP
通讯作者：
Dotto, GP
影响因子：
4.8
作者：
Fukata, Yuko;Iwanaga, Tsuyoshi;Fukata, Masaki
通讯作者：
Fukata, Masaki
影响因子：
4.8
作者：
Foitzik, K;Lindner, G;Paus, R
通讯作者：
Paus, R
影响因子：
10.5
作者：
Kadowaki, T;Wilder, E;Perrimon, N
通讯作者：
Perrimon, N
DOI：
10.1083/jcb.151.3.573
发表时间：
2000-10-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
DiColandrea T;Karashima T;Määttä A;Watt FM
通讯作者：
Watt FM