The endoribonuclease N4BP1 prevents psoriasis by controlling both keratinocytes proliferation and neutrophil infiltration.
The endoribonuclease N4BP1 prevents psoriasis by controlling both keratinocytes proliferation and neutrophil infiltration.
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核糖核酸内切酶 N4BP1 通过控制角质形成细胞增殖和中性粒细胞浸润来预防牛皮癣
DOI：
10.1038/s41419-021-03774-w
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发表时间：
2021-05-14
影响因子：
9
通讯作者：
Fan Y
中科院分区：
文献类型：
--
作者：
Gou C;Ni W;Ma P;Zhao F;Wang Z;Sun R;Wu Y;Wu Y;Chen M;Chen H;Zhang J;Shen Y;Xiao M;Lu C;Mao R;Fan Y
银屑病是一种常见的慢性皮肤病，其特征是过度增殖的表皮角质形成细胞与自身反应性免疫细胞之间的异常相互作用，其分子机制尚未完全阐明。N4 BP 1（NEDD 4-binding protein 1）长期以来被认为是一种免疫调节剂，但其生理作用尚未确定。在这里，我们发现N4 BP 1在皮肤中的表达在所有54个测试组织中是最高的，并且其表达在银屑病皮肤中进一步上调。与对照组相比，N4 BP 1缺陷型小鼠表现出正常的外观，但发展为严重和长期的IMQ诱导的银屑病样疾病。N4 BP 1主要表达于角质形成细胞，定位于细胞核。在N4 BP 1缺乏的皮肤中上调而非下调的基因在角质形成细胞增殖和分化中特异性富集。与对照组相比，N4 BP 1缺陷的原代角质形成细胞的增殖更快。在N4 BP 1消融后上调的基因高度富集在AP-1转录因子的靶标中。敲除N4 BP 1导致JunB和FosB上调，相反，N4 BP 1的过表达大大降低了它们的表达。此外，N4 BP 1与JunB和FosB编码mRNA结合，大大降低了它们的稳定性。此外，由于在中性粒细胞中的高表达，N4 BP 1通过靶向CXCL 1、CCL 20和S100 A8限制了中性粒细胞在血液中的存活和中性粒细胞在银屑病皮肤中的浸润。这些发现表明，N4 BP 1通过分别负调节JunB、FosB和CXCL 1来控制角质形成细胞和中性粒细胞的适当功能，这对银屑病的预防至关重要。
Psoriasis is a common chronic skin disease, characterized by abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells with not fully addressed molecular mechanism. N4BP1 (NEDD4-binding protein 1) is considered as an immune regulator for a long time but its physiological role is not determined yet. Here, we found that the expression of N4BP1 in skin was highest among all 54 tested tissues, and its expression was further upregulated in psoriatic skin. N4BP1-deficient mice exhibited normal grossly, but developed severe and prolonged IMQ-induced psoriasis-like disease comparing to controls. N4BP1 mainly expressed in keratinocytes and located on nucleus. Up- but not downregulated genes in N4BP1-deficient skin were specifically enriched in keratinocyte proliferation and differentiation. The proliferation of N4BP1-deficient primary keratinocytes was faster compared to that of controls. The upregulated genes upon ablation of N4BP1 were highly enriched in targets of AP-1 transcription factor. Knocking out N4BP1 resulted in upregulation of JunB and FosB, and conversely, overexpression of N4BP1 greatly reduced their expression. Furthermore, N4BP1 binds with JunB and FosB encoding mRNAs and greatly reduces their stability. In addition, with a high expression in neutrophils, N4BP1 limits survival of neutrophils in blood and infiltration of neutrophils in psoriatic skin by targeting CXCL1, CCL20, and S100A8. These findings demonstrate that N4BP1 controls the proper function of keratinocytes and neutrophils by negatively regulating JunB, FosB, and CXCL1, respectively, and that is critical for psoriasis prevention.
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DOI：
10.4049/jimmunol.1601551
发表时间：
2017-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Monin L;Gudjonsson JE;Childs EE;Amatya N;Xing X;Verma AH;Coleman BM;Garg AV;Killeen M;Mathers A;Ward NL;Gaffen SL
通讯作者：
Gaffen SL
影响因子：
2.4
作者：
Kim, Hee J.;Lebwohl, Mark G.
通讯作者：
Lebwohl, Mark G.
DOI：
10.1007/s00109-019-01853-2
发表时间：
2019-12
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
--
作者：
Konieczny P;Lichawska-Cieslar A;Kwiecinska P;Cichy J;Pietrzycka R;Szukala W;Declercq W;Devos M;Paziewska A;Rumienczyk I;Kulecka M;Mikula M;Fu M;Borowczyk J;Santamaria-Babí LF;Jura J
通讯作者：
Jura J
影响因子：
15.9
作者：
DANCEY, JT;DEUBELBEISS, KA;FINCH, CA
通讯作者：
FINCH, CA
DOI：
10.1111/bjd.19393
发表时间：
2021-04
期刊：
The British journal of dermatology
影响因子：
--
作者：
Gordon KB;Warren RB;Gottlieb AB;Blauvelt A;Thaçi D;Leonardi C;Poulin Y;Boehnlein M;Brock F;Ecoffet C;Reich K
通讯作者：
Reich K