1Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510 Japan.
2Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871 Japan.
Commun Biol. 2019 Jan 25;2:37. doi: 10.1038/s42003-018-0279-0. eCollection 2019.
Beclin 1 is a key regulator of autophagy and endocytosis. However, its autophagy-independent functions remain poorly understood. Here, we report that Beclin 1 regulates recycling endosome and is required for skin development in vivo. We first established keratinocyte-specific Beclin 1-knockout mice and found that these mutant mice died owing to severe impairment of epidermal barrier. Beclin 1 plays a role in autophagy and the endocytic pathway in cooperation with Atg14 and UVRAG, respectively, and keratinocyte-specific Atg14-knockout mice do not show any abnormal phenotypes, suggesting that Beclin 1 has a role in skin development via the endocytic pathway. Furthermore, we found that Beclin 1 deficiency causes mislocalization of integrins via a defect of recycling endosome, abnormal cell detachment of basal cells and their immature differentiation, and abnormal skin development. These results provide the first genetic evidence showing the roles of Beclin 1 in recycling endosome and skin development.
Beclin 1 是自噬和内吞作用的关键调节因子。然而，其非自噬依赖性功能仍知之甚少。在这里，我们报告 Beclin 1 调节再循环内体，并且对于体内皮肤发育是必需的。我们首先建立了角质形成细胞特异性 Beclin 1 敲除小鼠，并发现这些突变小鼠由于表皮屏障的严重损伤而死亡。Beclin 1 分别与 Atg14 和 UVRAG 在自噬和内吞途径中合作发挥作用，并且角质形成细胞特异性 Atg14 敲除小鼠没有显示出任何异常表型，这表明 Beclin 1 通过内吞途径在皮肤发育中发挥作用。此外，我们发现 Beclin 1 缺乏通过再循环内体的缺陷导致整合素的定位错误，基底细胞的异常细胞脱落及其不成熟的分化，以及皮肤的异常发育。这些结果提供了第一个遗传证据，表明 Beclin 1 在再循环内体和皮肤发育中的作用。
