Lichawska-Cieslar Agata, Szukala Weronika, Pilat Pawel, Eckhart Leopold, Szepietowski Jacek C, Jura Jolanta
Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, Krakow, 30-387, Poland.
Doctoral School of Exact and Natural Sciences, Jagiellonian University, Lojasiewicza 11, Krakow, 30-348, Poland.
Cell Commun Signal. 2025 Apr 8;23(1):175. doi: 10.1186/s12964-025-02184-1.
Monocyte chemoattractant protein-induced protein 3 (MCPIP3), also called Regnase-3 and encoded by the ZC3H12C gene, is a member of the MCPIP family of RNases. Previous studies showed that MCPIP1 in keratinocytes plays a pivotal role in the maintenance of skin integrity and immunological function. Given that the expression of MCPIP3, similar to that of MCPIP1, is increased in psoriatic lesions compared with uninvolved skin, a role of MCPIP3 in the regulation of keratinocyte and epidermal biology was hypothesized.
This study aimed to investigate the specific function of the MCPIP3 protein in the skin. The expression pattern of MCPIP3 was studied in normal human epidermal keratinocytes (NHEKs) subjected to in vitro differentiation and upon stimulation with proinflammatory factors. Mice with keratinocyte-specific deletion of MCPIP3 (Mcpip3Krt14; MCPIP3) were generated and characterized. The response of the skin of MCPIP3 mice to imiquimod (IMQ) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated. The expression levels of key modulators of keratinocyte proliferation and differentiation were measured in MCPIP3 model mice and in NHEKs transiently transfected with MCPIP3-specific siRNA. Reporter assays were used to identify direct targets of MCPIP3 nucleolytic activity.
In human keratinocytes, the expression of ZC3H12C/MCPIP3 was rapidly induced by stimulation with TPA, IL-17a, IL-36α, and TNF-α. Although mice with keratinocyte-specific deletion of MCPIP3 (MCPIP3) did not develop skin inflammation, they displayed abnormalities in skin morphology. Stimulation with IMQ and TPA exacerbated epidermal hyperplasia caused by keratinocyte-specific deficiency of MCPIP3 and led to abnormal epidermal differentiation. The expression levels of keratinocyte proliferation and differentiation markers, such as keratin-14, cyclin B1, involucrin, and the S100 calcium-binding proteins S100A7/A9, were increased in NHEKs in which MCPIP3 expression was silenced. MCPIP3 negatively regulates the level of cyclin B1 mRNA via direct nucleolytic cleavage within its 3' untranslated region.
The MCPIP3 protein modulates the balance of keratinocyte proliferation and differentiation and functions as a regulator of epidermal morphology in vivo.
单核细胞趋化蛋白诱导蛋白3（MCPIP3），也称为Regnase-3，由ZC3H12C基因编码，是核糖核酸酶MCPIP家族的成员。先前的研究表明，角质形成细胞中的MCPIP1在维持皮肤完整性和免疫功能方面起关键作用。鉴于与MCPIP1类似，MCPIP3在银屑病皮损中的表达相较于未受累皮肤有所增加，因此推测MCPIP3在调节角质形成细胞和表皮生物学方面发挥作用。
本研究旨在探究MCPIP3蛋白在皮肤中的具体功能。研究了MCPIP3在体外分化以及受到促炎因子刺激的正常人表皮角质形成细胞（NHEK）中的表达模式。构建并鉴定了角质形成细胞特异性缺失MCPIP3的小鼠（Mcpip3Krt14; MCPIP3）。研究了MCPIP3小鼠皮肤对咪喹莫特（IMQ）和十四酰佛波醇乙酯（TPA）的反应。在MCPIP3模型小鼠和用MCPIP3特异性siRNA瞬时转染的NHEK中测量角质形成细胞增殖和分化关键调节因子的表达水平。采用报告基因检测法鉴定MCPIP3核酸酶活性的直接靶点。
在人角质形成细胞中，用TPA、IL-17a、IL-36α和TNF-α刺激可迅速诱导ZC#FormatImgID_0#H12C/MCPIP3的表达。尽管角质形成细胞特异性缺失MCPIP3的小鼠（MCPIP3）未发生皮肤炎症，但它们表现出皮肤形态异常。用IMQ和TPA刺激加剧了由角质形成细胞特异性缺乏MCPIP3引起的表皮增生，并导致表皮分化异常。在MCPIP3表达被沉默的NHEK中，角质形成细胞增殖和分化标志物如角蛋白-14、细胞周期蛋白B1、兜甲蛋白以及S100钙结合蛋白S100A7/A9的表达水平升高。MCPIP3通过在其3'非翻译区内直接进行核酸酶切割来负调控细胞周期蛋白B1 mRNA的水平。
MCPIP3蛋白调节角质形成细胞增殖和分化的平衡，并在体内作为表皮形态的调节因子发挥作用。
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