Trim32 Regulation of Piasy in Skin Homeostasis

Trim32 对 Piasy 皮肤稳态的调节

• 批准号: 7869371
• 负责人: MOLLY F. KULESZ-MARTIN
• 金额: $ 34.3万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869371
• 关键词: 19p13; Acanthosis; Apoptosis; Apoptotic; Atopic Dermatitis; CCL20 gene; CCR6 gene; Cell Survival; Cells; Chromosomes; Death Rate; Dendritic Cells; Dermal; Development; Disease; Environment; Enzymes; Epidermis; Equilibrium; Feedback; Figs - dietary; Fostering; Genes; Growth; Homeostasis; Human; Hyperplasia; IL17 gene; ITGAX gene; Immune; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-17; Knockout Mice; Lead; Lesion; Ligase; Link; Lymphocyte; Mediating; Modeling; Molecular; Mus; NF-kappa B; Organ; Parakeratosis; Partner in relationship; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Production; Proteins; Psoriasiform Dermatitis; Psoriasis; Regulation; Role; Severities; Skin; Symptoms; Testing; Th2 Cells; Therapeutic; Tissue Sample; Transgenic Mice; Up-Regulation; base; chemokine; cytokine; human disease; in vivo; inhibitor/antagonist; interleukin-22; interleukin-23; keratinocyte; mouse model; public health relevance; response; skin disorder; transcription factor; treatment strategy; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): There is a vicious circle in psoriasis that disrupts epidermal homeostasis through alterations in keratinocytes (hyperproliferation, parakeratosis) and immunocytes (infiltration and activation). While it is well known that uncontrolled keratinocyte proliferation is largely driven by pro-inflammatory cytokines from the immunocytes, the functional role of keratinocytes in the recruitment and activation of immunocytes is poorly understood. We have discovered intriguing links between Trim32 (an E3 ubiquitin ligase), its substrate Piasy (an E3 SUMO ligase), and psoriasis. Trim32 is elevated in psoriasis tissue samples compared to non-lesional control epidermis. Trim32 negatively regulates the pro-apoptotic Piasy protein, a repressor of NF-kB, STAT, and SMAD transcription factors that have been implicated in the pathogenesis of psoriasis. The Piasy gene resides in the PSORS6 susceptibility locus on chromosome 19p13, although the significance of this remains to be determined. We have found that Trim32 activates and Piasy inhibits keratinocyte production of CCL20, a chemokine increased in psoriatic lesions that is a major factor in recruitment of dendritic cells and Th17 lymphocytes to the skin. The CCL20 induction by TNFa and IL17 cytokines is mediated through the activation of NF-kB. These findings lead us to hypothesize that Trim32 and Piasy are part of a positive feedback loop of CCL20 overproduction by keratinocytes and Th17 activation that contributes to the cycle of psoriasis. Initial evidence suggests that Trim32 is not simply a general marker of epidermal hyperplasia because its elevation in psoriasis, recognized as a Th17 disease, is not shared by atopic dermatitis, recognized as a Th2 cell disease, and because upregulation of CCL20 in keratinocytes responds to Th17 but not Th1 or Th2 cytokines. We propose to define the role of Trim32 and Piasy in psoriasis according to the following aims: 1) determine molecular pathways of Trim32 and Piasy regulation of CCL20 production in keratinocytes in response to Th17 cytokines, in particular through the NF-kB pathway, and evaluate the effects of Trim32 and Piasy on the dermal recruitment of CD11c+ dendritic cells and Th17 cells; 2) explore the functional role of Trim32 and Piasy in keratinocyte survival and epidermal acanthosis in response to Th17 activation, using in vitro and in vivo approaches, and determine the impact of Trim32 KO and Piasy KO on the severity of phenotypes in two mouse models of psoriasiform dermatitis; and 3) evaluate the role of Trim32 and Piasy in CCL20 expression, inflammation and keratinocyte apoptosis in psoriasis and atopic dermatitis. Ultimately, these studies may impact our understanding of the molecular mechanisms of psoriasis as distinct from atopic dermatitis and lead to rational improvement of treatment strategies for psoriasis patients. PUBLIC HEALTH RELEVANCE: Psoriasis is a skin disease in which skin cells lose the proper balance between their growth and death rates, and certain immune system cells are over-active. We have found that the enzyme "Trim32" is overly active in psoriasis, causing loss of the protein Piasy, a major inhibitor of certain genes that are active in human psoriasis and that can cause psoriasis-like symptoms in mice, leading to the production of proteins that attract more immune cells to the skin, making the symptoms worse. Understanding how Trim32 and Piasy control skin cell survival and skin inflammation promises new ways to treat psoriasis and other human diseases of the skin, as well as inflammatory diseases in other organs of the body.

描述（由申请人提供）：牛皮癣中有一个恶性循环，通过角质细胞的改变（高增殖，parakeratisos）和免疫细胞（浸润和激活）来破坏表皮稳态。众所周知，不受控制的角质形成细胞增殖主要是由免疫细胞促炎性细胞因子驱动的，但角质形成细胞在募集和激活免疫细胞中的功能作用知之甚少。我们发现了TRIM32（E3泛素连接酶），其底物Piasy（E3 Sumo连接酶）和牛皮癣之间的有趣联系。与非静电对照表皮相比，牛皮癣组织样品中的TRIM32升高。 TRIM32负调控促凋亡的piasy蛋白，这是NF-KB，STAT和SMAD转录因子的阻遏物，与牛皮癣的发病机理有关。尽管有待确定的重要性尚有待确定，但Piasy基因驻留在19p13染色体上的Psors6易感基因座上。我们发现，TRIM32激活和PIASY抑制CCL20的角质形成细胞的产生，银屑病病变的趋化因子增加，这是树突状细胞募集和皮肤Th17淋巴细胞的主要因素。 TNFA和IL17细胞因子的CCL20诱导是通过NF-KB的激活介导的。这些发现使我们假设Trim32和Piasy是角质形成细胞和Th17激活的CCL20阳性反馈回路的一部分，这有助于牛皮癣的循环。最初的证据表明，TRIM32不仅是表皮增生的一般标志物，因为其牛皮癣的升高（被认为是Th17疾病）并未被特应性皮炎（被认为是TH2细胞疾病）共享，并且由于角质生物的上调CCL20在角膜菌中的上调对TH17而言反应于Th17，但对TH17或TH1或Th2 Cyt2 cyt2 cytokines。 We propose to define the role of Trim32 and Piasy in psoriasis according to the following aims: 1) determine molecular pathways of Trim32 and Piasy regulation of CCL20 production in keratinocytes in response to Th17 cytokines, in particular through the NF-kB pathway, and evaluate the effects of Trim32 and Piasy on the dermal recruitment of CD11c+ dendritic cells and Th17细胞； 2）探索Trim32和Piasy在角质形成细胞存活中的功能作用以及使用体外和体内方法对Th17激活的反应，并确定Trim32 KO和PIASY KO对两种小鼠模型在Psorias sifferias形成的小鼠模型中的影响； 3）评估TRIM32和PIASY在CCL20表达，炎症和角质形成细胞凋亡中在牛皮癣和特应性皮炎中的作用。最终，这些研究可能会影响我们对牛皮癣分子机制的理解，这与特应性皮炎不同，并使牛皮癣患者的治疗策略有理改善。公共卫生相关性：牛皮癣是一种皮肤病，皮肤细胞在生长和死亡率之间失去适当的平衡，并且某些免疫系统细胞过于活跃。我们已经发现，酶“ TRIM32”在牛皮癣中过于活跃，导致蛋白质piasy的丧失，蛋白质PIASY是某些活性在人牛皮癣中的主要抑制剂，并且会导致小鼠类似牛皮癣的症状，从而导致蛋白质产生的蛋白质产生，从而使更多的免疫细胞吸引皮肤，从而使症状更糟。了解TRIM32和PIASY CONTROL皮肤细胞的存活和皮肤炎症如何有望治疗牛皮癣和皮肤其他人类疾病的新方法，以及人体其他器官中的炎症性疾病。