Evans Trent D, Sergin Ismail, Zhang Xiangyu, Razani Babak
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sci Signal. 2017 Feb 28;10(468):eaag2298. doi: 10.1126/scisignal.aag2298.
The accumulation of damaged or excess proteins and organelles is a defining feature of metabolic disease in nearly every tissue. Thus, a central challenge in maintaining metabolic homeostasis is the identification, sequestration, and degradation of these cellular components, including protein aggregates, mitochondria, peroxisomes, inflammasomes, and lipid droplets. A primary route through which this challenge is met is selective autophagy, the targeting of specific cellular cargo for autophagic compartmentalization and lysosomal degradation. In addition to its roles in degradation, selective autophagy is emerging as an integral component of inflammatory and metabolic signaling cascades. In this Review, we focus on emerging evidence and key questions about the role of selective autophagy in the cell biology and pathophysiology of metabolic diseases such as obesity, diabetes, atherosclerosis, and steatohepatitis. Essential players in these processes are the selective autophagy receptors, defined broadly as adapter proteins that both recognize cargo and target it to the autophagosome. Additional domains within these receptors may allow integration of information about autophagic flux with critical regulators of cellular metabolism and inflammation. Details regarding the precise receptors involved, such as p62 and NBR1, and their predominant interacting partners are just beginning to be defined. Overall, we anticipate that the continued study of selective autophagy will prove to be informative in understanding the pathogenesis of metabolic diseases and to provide previously unrecognized therapeutic targets.
受损或过量蛋白质及细胞器的积累是几乎每个组织中代谢性疾病的一个决定性特征。因此，维持代谢稳态的一个核心挑战是识别、隔离和降解这些细胞成分，包括蛋白质聚集体、线粒体、过氧化物酶体、炎性小体和脂滴。应对这一挑战的主要途径是选择性自噬，即将特定的细胞货物靶向进行自噬分隔和溶酶体降解。除了其在降解中的作用外，选择性自噬正成为炎症和代谢信号级联反应的一个不可或缺的组成部分。在本综述中，我们重点关注关于选择性自噬在肥胖、糖尿病、动脉粥样硬化和脂肪性肝炎等代谢性疾病的细胞生物学和病理生理学中的作用的新证据和关键问题。这些过程中的关键参与者是选择性自噬受体，广义上定义为既能识别货物又能将其靶向自噬体的衔接蛋白。这些受体中的其他结构域可能允许将有关自噬通量的信息与细胞代谢和炎症的关键调节因子整合起来。关于具体涉及的受体，如p62和NBR1，以及它们主要的相互作用伙伴的详细信息才刚刚开始被确定。总体而言，我们预计对选择性自噬的持续研究将有助于理解代谢性疾病的发病机制，并提供以前未被认识的治疗靶点。
