Autophagy is a versatile degradation system for maintaining cellular homeostasis whereby cytosolic materials are sequestered in a double-membrane autophagosome and subsequently delivered to lysosomes, where they are broken down. In multicellular organisms, newly formed autophagosomes undergo a process called ‘maturation’, in which they fuse with vesicles originating from endolysosomal compartments, including early/late endosomes and lysosomes, to form amphisomes, which eventually become degradative autolysosomes. This fusion process requires the concerted actions of multiple regulators of membrane dynamics, including SNAREs, tethering proteins and RAB GTPases, and also transport of autophagosomes and late endosomes/lysosomes towards each other. Multiple mechanisms modulate autophagosome maturation, including post-translational modification of key components, spatial distribution of phosphoinositide lipid species on membranes, RAB protein dynamics, and biogenesis and function of lysosomes. Nutrient status and various stresses integrate into the autophagosome maturation machinery to coordinate the progression of autophagic flux. Impaired autophagosome maturation is linked to the pathogenesis of various human diseases, including neurodegenerative disorders, cancer and myopathies. Furthermore, invading pathogens exploit various strategies to block autophagosome maturation, thus evading destruction and even subverting autophagic vacuoles (autophagosomes, amphisomes and autolysosomes) for survival, growth and/or release. Here, we discuss the recent progress in our understanding of the machinery and regulation of autophagosome maturation, the relevance of these mechanisms to human pathophysiology and how they are harnessed by pathogens for their benefit. We also provide perspectives on targeting autophagosome maturation therapeutically.

自噬是一种用于维持细胞稳态的多功能降解系统，其中细胞溶质物质被隔离在双膜自噬体中，随后被输送到溶酶体，在那里它们被分解。在多细胞生物中，新形成的自噬体经历了一个称为“成熟”的过程，其中它们与源自内溶酶体区室的囊泡融合，包括早期/晚期内体和溶酶体，形成两性体，最终成为降解性自溶酶体。这种融合过程需要多种膜动力学调节剂的协同作用，包括 SNARE、束缚蛋白和 RAB GTP酶，以及自噬体和晚期内体/溶酶体相互转运。多种机制调节自噬体成熟，包括关键成分的翻译后修饰、磷酸肌醇脂质种类在膜上的空间分布、RAB 蛋白动力学以及溶酶体的生物发生和功能。营养状况和各种压力整合到自噬体成熟机制中以协调自噬通量的进展。自噬体成熟受损与各种人类疾病的发病机制有关，包括神经退行性疾病、癌症和肌病。此外，入侵病原体利用各种策略来阻止自噬体成熟，从而避免破坏甚至破坏自噬泡（自噬体、两性体和自溶酶体）以实现生存、生长和/或释放。在这里，我们讨论了我们对自噬体成熟机制和调控的理解的最新进展，这些机制与人类病理生理学的相关性以及病原体如何利用它们来获益。我们还提供了治疗靶向自噬体成熟的观点。