Institute of Immunology and Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
Department of Dermatology and Venereology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
EMBO Rep. 2021 May 5;22(5):e52063. doi: 10.15252/embr.202052063. Epub 2021 Mar 26.
Psoriasis is mainly characterized by abnormal hyperplasia of keratinocytes and immune cells infiltrating into the dermis and epidermis. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is a highly conserved HECT type E3 ligase that plays an important role in regulating physiological and pathological processes. Here, we identify NEDD4L as a negative regulator of psoriasis. Nedd4l significantly inhibits imiquimod (IMQ)-induced skin hyperplasia, and this effect is attributed to the inhibitory effect of NEDD4L on IL-6/GP130 signaling in keratinocytes. Mechanistically, NEDD4L directly interacts with GP130 and mediates its Lys-27-linked ubiquitination and proteasomal degradation. Moreover, the expression of NEDD4L is downregulated in the epidermis from IMQ-treated mice and psoriasis patients and negatively correlates with the protein levels of GP130 and p-STAT3 in clinical samples. Collectively, we uncover an inhibitory role of NEDD4L in the pathogenesis of psoriasis and suggest a new therapeutic strategy for the treatment of psoriasis.
银屑病主要表现为角质形成细胞和免疫细胞异常增生，浸润真皮和表皮。神经前体细胞表达发育下调 4 样蛋白（NEDD4L）是一种高度保守的 HECT 型 E3 连接酶，在调节生理和病理过程中发挥重要作用。在这里，我们鉴定出 NEDD4L 是银屑病的负调控因子。Nedd4l 显著抑制咪喹莫特（IMQ）诱导的皮肤过度增生，这一作用归因于 NEDD4L 对角质形成细胞中 IL-6/GP130 信号的抑制作用。在机制上，NEDD4L 直接与 GP130 相互作用，并介导其 Lys-27 连接的泛素化和蛋白酶体降解。此外，在 IMQ 处理的小鼠和银屑病患者的表皮中，NEDD4L 的表达下调，与临床样本中 GP130 和 p-STAT3 的蛋白水平呈负相关。综上所述，我们揭示了 NEDD4L 在银屑病发病机制中的抑制作用，并为银屑病的治疗提供了一种新的治疗策略。
