Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.
Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China.
Exp Dermatol. 2023 Nov;32(11):1960-1970. doi: 10.1111/exd.14922. Epub 2023 Sep 8.
PKM2 mediates the Warburg effects and is crucial for tumorigenesis, but its role in hyperplastic skin disorders remains elusive. In this study, we investigated the function of PKM2 in psoriatic keratinocytes. We found that PKM2 expression and its nuclear translocation were induced in the epidermis of psoriasis patients, contributing to aerobic glycolysis and cell growth. Moreover, mass spectrometry combined with immunoprecipitation analysis revealed that PKM2 could interact with TRIM33, an E3 ubiquitin ligase in the nucleus, and this interaction is critical for the nuclear retention of PKM2. As a result of TRIM33-mediated ubiquitination, PKM2 nuclear protein kinase function is promoted, thus leading to the phosphorylation of STAT3. In addition, blocking PKM2 nuclear translocation abrogated TRIM33-triggered glycolysis and cell proliferation in keratinocytes. Taken together, our experiments demonstrate that ubiquitination regulates the nuclear retention of PKM2 in keratinocytes. Moreover, our results highlight a novel mechanism accounting for the metabolic reprogramming of keratinocytes in psoriasis patients.
PKM2 介导了瓦博格效应，对肿瘤发生至关重要，但它在增生性皮肤疾病中的作用仍不清楚。在这项研究中，我们研究了 PKM2 在银屑病角质形成细胞中的功能。我们发现 PKM2 的表达及其核易位在银屑病患者的表皮中被诱导，促进有氧糖酵解和细胞生长。此外，质谱联用免疫沉淀分析表明 PKM2 可以与核内的 E3 泛素连接酶 TRIM33 相互作用，这种相互作用对于 PKM2 的核保留至关重要。由于 TRIM33 介导的泛素化，PKM2 核蛋白激酶功能得到促进，从而导致 STAT3 的磷酸化。此外，阻断 PKM2 核易位可消除 TRIM33 触发的角质形成细胞中的糖酵解和增殖。总之，我们的实验证明泛素化调节了角质形成细胞中 PKM2 的核保留。此外，我们的结果强调了一种新的机制，解释了银屑病患者角质形成细胞的代谢重编程。
