Editorial: STATus of STAT3 in Psoriatic Arthritis.
Editorial: STATus of STAT3 in Psoriatic Arthritis.
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社论：STAT3 在银屑病关节炎中的现状。
DOI：
10.1002/art.40445
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Mountz,JohnD
中科院分区：
文献类型：
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作者：
Mountz,JohnD
关节疾病和末端病出现在约三分之一的牛皮癣患者中，通常出现在牛皮癣的皮肤症状之前。银屑病皮肤病的发病机制与银屑病关节炎的发病机制之间的关系尚未明确，银屑病皮肤病是否会引发关节疾病的发展这一核心问题仍未得到解决。已经证明，利用针对角质形成细胞的STAT3C构建的信号转导和转录激活因子3(STAT3)的结构性、高表达足以诱导皮肤银屑病样皮损。当结合突变形式的糖蛋白130(Gp130)等位基因(一种细胞因子受体信号转导)的全球表达时，STAT3C结构会导致小鼠关节炎[1，2]。在本期中，Yang及其同事介绍了一种新的小鼠模型，该模型独一无二，它体现了皮肤病和牛皮癣关节炎的所有主要特征，包括皮肤病、关节疾病和终末期疾病，以及骨量减少[3]。该模型也基于STAT3C构建的STAT3的结构性高表达，但在这种情况下，构建物的靶向性足以诱导所有的表达。STAT3信号在正常细胞功能中发挥关键作用，包括细胞生长、存活、增殖、凋亡和炎症。它被多种细胞因子和生长因子激活，通过JAK介导的酪氨酸705的磷酸化或丝氨酸727的磷酸化，通过各种丝氨酸/苏氨酸蛋白激酶(MAPK、mTOR和PKCδ)激活，这是获得最大转录活性所必需的。STAT3蛋白在细胞质中以不活跃的单体形式存在，直到它们被磷酸化，从而促进它们的二聚化。二聚体被转移到细胞核，在那里它们与调节一系列基因转录的特定DNA元件结合。大约20年前，Darnell和他的同事通过在STAT3分子SH2结构域的c-末端环中用半胱氨酸残基取代酪氨酸，设计出了可构成二聚化的STAT3分子STAT3C[4]。STAT3C被证明驱动转录，不仅刺激细胞的生长和增殖，而且促进转化。随后，在几种人类恶性肿瘤中发现了自然发生的STAT3的结构性激活。不应将STAT3C与STAT3功能的自然亚型混淆，后者是由STAT3外显子23的选择性剪接事件引起的。这导致缺乏丝氨酸的STAT3(STAT3β)[5]的截短形式的表达。尽管最初被认为是以显性-负性方式起作用，但它是一个生物活性分子，能够调节STAT3的致瘤功能。这两种异构体的不同表达只代表了调控STAT3信号的大小并改变其对
Joint disease and enthesopathy are seen in about one-third of patients with psoriasis and are usually preceded by the cutaneous manifestations of psoriasis. The relationships between the pathogenesis of psoriatic skin disease and the pathogenesis of psoriatic arthritis have not been defined, however, and the central question as to whether psoriatic skin disease initiates development of joint disease remains unresolved. It has been shown that constitutive, hyperexpression of signal transducers and activators of transcription 3 (STAT3) using a STAT3C construct targeted to keratinocytes is sufficient to induce cutaneous psoriasis-like lesions. When combined with global expression of a mutant form of the glycoprotein 130 (gp130) allele, a cytokine receptor signal transducer, the STAT3C construct leads to arthritis in mice [1, 2]. In this issue, Yang and colleagues introduce a new mouse model that is unique in that it embodies all the major features of cutaneous psoriasis and psoriatic arthritis including skin disease, joint disease and an enthesopathy, as well as osteopenia [3]. This model also is based on constitutive, hyperexpression of STAT3 using the STAT3C construct but in this case the targeting of the construct to CD4+ T cells has been found to be sufficient to induce all the manifestations.STAT3 signaling plays a key role in normal cell functions including cell growth, survival, proliferation, apoptosis and inflammation. It is activated by numerous cytokines and growth factors through JAK-mediated phosphorylation of tyrosine 705 or phosphorylation of serine 727 through a variety of serine/threonine protein kinases (MAP kinase, mTOR and PKCδ), which is required for maximal STAT3 transcriptional activity. The STAT3 proteins occur as inactive monomers in the cytoplasm until their phosphorylation which prompts their dimerization. The dimers are translocated to the nucleus where they bind to specific DNA elements that regulate transcription of an array of genes. Almost two decades ago, Darnell and co-workers engineered the constitutively dimerizable STAT3 molecule, STAT3C, by substituting cysteine residues for tyrosine within the c-terminal loop of the SH2 domain of the STAT3 molecule [4]. STAT3C was shown to drive transcription, stimulating not only cell growth and proliferation but also promoting transformation. Subsequently, naturally occurring constitutive activation of STAT3 has been identified in several human malignancies. STAT3C should not be confused with the naturally occurring isoforms of STAT3 function that result from an alternative splicing event of STAT3 at exon 23. This results in the expression of a truncated form of STAT3 (STAT3β)[5] that lacks serine 727. Although initially thought to act in a dominant-negative manner, it is a biologically active molecule capable of modulating the tumorigenic functions of STAT3. The differential expression of these two isoforms represents just one aspect of the complex network of mechanisms that regulate the magnitude of STAT3 signaling and modify its effects on