上皮细胞黏着结构半桥粒在热激保护中的作用机制研究

Hemidesmosome is a major attachment complex connecting epithelial cells to the basement membrane. Recent findings reveal that hemidesmosome is not only responsible for anchoring, but also involved in multiple biological processes, such as immune response and mechanotransduction. However, there are rarely any reports about the function of hemidesmosomes in cytoprotection against heat. C. elegans is an ideal model system to study hemidesmosomes, because its hemidesmosomes have highly similarity to their mammalian counterparts. We utilized this model and found that a small heat shock protein, HSP-43, binds to C. elegans hemidesmosomes and plays an important role to protect the organism from heat stress. Our further study revealed that the loss of HSP-43 does not affect the stability of hemidesmosomes under heat stress，indicating that hemidesmosomes are not the downstream substrate of HSP-43. However, the localization on hemidesmosomes of HSP-43 affects its function in protection against heat stress. Therefore，we predict that hemidesmosomes may be involved in heat resistance as the upstream regulator of HSP-43. We will further confirm this hypothesis, investigate the underlying mechanisms how hemidesmosomes regulate the thermotolerance through small heat shock protein and reveal the physiological significance of this regulation mechanism. Our studies may refresh our knowledge about hemidesmosome function and the regulation mechanism of small heat shock protein.

半桥粒是位于上皮细胞与基底膜之间的主要黏着结构。最近的研究显示半桥粒不仅负责细胞黏着，还参与调节其他生命过程，如免疫应答、机械力信号转导等。但是半桥粒在热激保护中的作用还鲜有报道。秀丽线虫上皮细胞中的半桥粒与哺乳动物高度相似，是研究半桥粒结构功能的理想模型。我们利用该模型发现半桥粒上结合着一种小热休克蛋白HSP-43，并且HSP-43的缺失显著降低了机体的热耐受能力。我们进一步发现HSP-43的缺失不影响半桥粒在热激过程中的稳定性，说明半桥粒并不是HSP-43的下游靶标。但是HSP-43的半桥粒定位却影响其热激保护功能。因此我们推测半桥粒可能作为HSP-43的上游调控元件参与热激保护过程。接下来，我们将验证这一假设，并进一步深入解析半桥粒通过小热休克蛋白调控热激保护过程的具体分子机制，以及该机制的生理意义。该研究成果将进一步刷新我们对半桥粒功能以及小热休克蛋白调节机制的认识。

半桥粒是联结上皮细胞层与细胞外基质的重要锚定结构。越来越多的证据表明半桥粒不仅维持组织结构的机械稳定性，还介导一些与细胞支撑结构无关的生理功能。但是对细胞黏着结构在应激保护中的具体作用机制却知之甚少。在本项目中，我们发现半桥粒在正常情况下会执行一个类似急救仓的功能，储备大量的小热休克蛋白HSP-43，限制其功能并保护其不被降解，而在热激情况下迅速将其释放以实现细胞对急性热损伤的快速耐受。与小热休克蛋白转录上调的经典热休克反应相比，这种预存于细胞黏着结构的小热休克蛋白的转位活化机制为细胞提供了更为及时的保护。上述成果不仅刷新了我们对细胞黏着结构的应激保护功能的认识，也从全新的视角揭示了持续高表达的小热休克蛋白是如何被激活的。同时强调了细胞结构完整性在应激抵抗和损伤控制中的重要性，为半桥粒和热激损伤相关疾病的治疗提供了理论依据。