Hosaka Yusuke, Araya Jun, Fujita Yu, Kuwano Kazuyoshi
Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
Inflamm Regen. 2021 Oct 1;41(1):29. doi: 10.1186/s41232-021-00180-9.
Autophagy is a highly conserved mechanism of delivering cytoplasmic components for lysosomal degradation. Among the three major autophagic pathways, chaperone-mediated autophagy (CMA) is primarily characterized by its selective nature of protein degradation, which is mediated by heat shock cognate 71 kDa protein (HSC70: also known as HSPA8) recognition of the KFERQ peptide motif in target proteins. Lysosome-associated membrane protein type 2A (LAMP2A) is responsible for substrate binding and internalization to lysosomes, and thus, the lysosomal expression level of LAMP2A is a rate-limiting factor for CMA. Recent advances have uncovered not only physiological but also pathological role of CMA in multiple organs, including neurodegenerative disorders, kidney diseases, liver diseases, heart diseases, and cancers through the accumulation of unwanted proteins or increased degradation of target proteins with concomitant metabolic alterations resulting from CMA malfunction. With respect to pulmonary disorders, the involvement of CMA has been demonstrated in lung cancer and chronic obstructive pulmonary disease (COPD) pathogenesis through regulating apoptosis. Further understanding of CMA machinery may shed light on the molecular mechanisms of refractory disorders and lead to novel treatment modalities through CMA modulation.
自噬是一种高度保守的机制，用于将细胞质成分输送到溶酶体进行降解。在三种主要的自噬途径中，伴侣介导的自噬（CMA）主要以其蛋白质降解的选择性为特征，这是由热休克同源71 kDa蛋白（HSC70：也称为HSPA8）识别靶蛋白中的KFERQ肽基序介导的。溶酶体相关膜蛋白2A型（LAMP2A）负责底物与溶酶体的结合和内化，因此，LAMP2A的溶酶体表达水平是CMA的限速因素。最近的研究进展不仅揭示了CMA在包括神经退行性疾病、肾脏疾病、肝脏疾病、心脏疾病和癌症在内的多个器官中的生理作用，还揭示了其病理作用，这些作用是通过不需要的蛋白质积累或由于CMA功能障碍导致的伴随代谢改变而增加靶蛋白降解引起的。关于肺部疾病，通过调节细胞凋亡，已证明CMA参与肺癌和慢性阻塞性肺疾病（COPD）的发病机制。对CMA机制的进一步了解可能有助于揭示难治性疾病的分子机制，并通过调节CMA导致新的治疗方式。
