School of Life, Health and Chemical Sciences, The Open University, MK7 6AA, UK.
School of Life, Health and Chemical Sciences, The Open University, MK7 6AA, UK.
Cell Calcium. 2018 Mar;70:32-46. doi: 10.1016/j.ceca.2017.08.005. Epub 2017 Aug 19.
Macroautophagy (hereafter called 'autophagy') is a cellular process for degrading and recycling cellular constituents, and for maintenance of cell function. Autophagy initiates via vesicular engulfment of cellular materials and culminates in their degradation via lysosomal hydrolases, with the whole process often being termed 'autophagic flux'. Autophagy is a multi-step pathway requiring the interplay of numerous scaffolding and signalling molecules. In particular, orthologs of the family of ∼30 autophagy-regulating (Atg) proteins that were first characterised in yeast play essential roles in the initiation and processing of autophagic vesicles in mammalian cells. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a master regulator of the canonical autophagic response of cells to nutrient starvation. In addition, AMP-activated protein kinase (AMPK), which is a key sensor of cellular energy status, can trigger autophagy by inhibiting mTOR, or by phosphorylating other downstream targets. Calcium (Ca) has been implicated in autophagic signalling pathways encompassing both mTOR and AMPK, as well as in autophagy seemingly not involving these kinases. Numerous studies have shown that cytosolic Ca signals can trigger autophagy. Moreover, introduction of an exogenous chelator to prevent cytosolic Ca signals inhibits autophagy in response to many different stimuli, with suggestions that buffering Ca affects not only the triggering of autophagy, but also proximal and distal steps during autophagic flux. Observations such as these indicate that Ca plays an essential role as a pro-autophagic signal. However, cellular Ca signals can exert anti-autophagic actions too. For example, Ca channel blockers induce autophagy due to the loss of autophagy-suppressing Ca signals. In addition, the sequestration of Ca by mitochondria during physiological signalling appears necessary to maintain cellular bio-energetics, thereby suppressing AMPK-dependent autophagy. This article attempts to provide an integrated overview of the evidence for the proposed roles of various Ca signals, Ca channels and Ca sources in controlling autophagic flux.
自噬（以下简称自噬）是一种降解和回收细胞成分的细胞过程，有助于维持细胞功能。自噬通过囊泡吞噬细胞物质起始，最终通过溶酶体水解酶降解，整个过程通常被称为“自噬流”。自噬是一个多步骤的途径，需要许多支架和信号分子的相互作用。特别是，在酵母中首次被鉴定的约 30 种自噬调节（Atg）蛋白家族的同源物在哺乳动物细胞中自噬囊泡的起始和加工中发挥着重要作用。丝氨酸/苏氨酸激酶 mTOR（雷帕霉素的作用靶点）是细胞对营养饥饿的经典自噬反应的主要调节剂。此外，作为细胞能量状态的关键传感器的 AMP 激活的蛋白激酶（AMPK）可以通过抑制 mTOR 或磷酸化其他下游靶点来触发自噬。钙（Ca）已被牵连到包含 mTOR 和 AMPK 的自噬信号通路中，以及似乎不涉及这些激酶的自噬中。许多研究表明，细胞质 Ca 信号可以触发自噬。此外，引入外源螯合剂以防止细胞质 Ca 信号抑制对许多不同刺激的自噬，表明缓冲 Ca 不仅影响自噬的触发，还影响自噬流的近端和远端步骤。这些观察结果表明，Ca 作为一种促进自噬的信号发挥着重要作用。然而，细胞 Ca 信号也可以发挥抗自噬作用。例如，由于自噬抑制性 Ca 信号的丧失，Ca 通道阻滞剂会诱导自噬。此外，在生理信号期间，线粒体对 Ca 的隔离似乎对于维持细胞生物能量是必要的，从而抑制 AMPK 依赖性自噬。本文试图提供一个综合的概述，说明各种 Ca 信号、Ca 通道和 Ca 来源在控制自噬流中的作用的证据。
