HSPA1A Protects Cells from Thermal Stress by Impeding ESCRT-0-Mediated Autophagic Flux in Epidermal Thermoresistance
HSPA1A Protects Cells from Thermal Stress by Impeding ESCRT-0-Mediated Autophagic Flux in Epidermal Thermoresistance
复制标题
HSPA1A 通过阻碍表皮耐热性中 ESCRT-0 介导的自噬通量来保护细胞免受热应激
DOI：
10.1016/j.jid.2020.05.105
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发表时间：
2021
影响因子：
6.5
通讯作者：
Yao Min
中科院分区：
文献类型：
--
作者：
Wu Shan;Pei Qing;Ni Wei;Fu Xiujun;Zhang Wen;Song Chenlu;Peng Yinbo;Guo Qige;Dong Jiying;Yao Min
热阻是一种与皮肤美容和肿瘤切除的无创激光治疗相关的生理现象，尽管其潜在机制仍然难以捉摸。我们假设 HSPA1A 可能通过降低 ESCRT-0 和/或 STAM2 水平来调节自噬，这可能导致细胞死亡的热保护。在这项研究中，我们发现通过在 45 °C 下加热 10 分钟，可以在小鼠表皮组织和 HaCaT 细胞中诱导耐热性。此外，耐热小鼠表皮和 HaCaT 细胞中的 HSPA1A 水平升高。 HSPA1A 基因的敲低或过表达测定证明，HSPA1A 高度参与保护细胞免受热细胞毒性。此外，耐热细胞中 ESCRT-0 和 STAM2 水平显着降低，这是由 HSPA1A 与 STAM2 结合介导的，特别是通过 HSPA1A 氨基酸 395-509 介导。此外，响应 HSPA1A-STAM2 结合而导致 ESCRT-0 和/或 STAM2 的丢失，通过阻碍自噬体-溶酶体融合并消除细胞耐热性中的自噬流来调节自噬，显着降低热细胞毒性并促进细胞存活。据我们所知，之前没有报道过 HSPA1A–ESCRT-0 和/或 STAM2 通过抑制自噬流来调节热诱导的抵抗力。总之，本研究的结果表明，热阻机制可能与无创或微创热疗法具有临床相关性。
Thermoresistance is a physiological phenomenon relevant to noninvasive laser treatments for skin esthetics and tumor removal, although the underlying mechanism remains elusive. We hypothesized that HSPA1A may regulate autophagy by reducing ESCRT-0 and/or STAM2 levels, which could lead to thermal protection from cell death. In this study, we showed that thermoresistance was induced in mouse epidermal tissue and HaCaT cells by heating at 45 °C for 10 minutes. Moreover, HSPA1A levels were increased in thermoresistant mouse epidermis and HaCaT cells. HSPA1A was highly involved in protecting cells from thermal cytotoxicity, as evidenced by the knockdown or overexpression assays of theHSPA1Agene. In addition, ESCRT-0 and STAM2 levels were dramatically decreased in thermoresistant cells, which was mediated by HSPA1A binding to STAM2, particularly through HSPA1A amino acids 395‒509. Furthermore, the loss of ESCRT-0 and/or STAM2 in response to HSPA1A–STAM2 binding regulated autophagy by impeding autophagosome‒lysosome fusion and abolishing autophagic flux in cellular thermoresistance, significantly reducing thermal cytotoxicity and promoting cell survival. To our knowledge, it is previously unreported that HSPA1A–ESCRT-0 and/or STAM2 modulates heat-induced resistance by inhibiting autophagic flux. In summary, the results of this study demonstrate that the mechanisms of thermoresistance may have clinical relevance for noninvasive or minimally invasive thermal therapeutics.