cAMP-Protein Kinase A and Stress-Activated MAP Kinase signaling mediate transcriptional control of autophagy in fission yeast during glucose limitation or starvation

Macroautophagy/autophagy is an essential adaptive physiological response in eukaryotes induced during nutrient starvation, including glucose, the primary immediate carbon and energy source for most cells. Although the molecular mechanisms that induce autophagy during glucose starvation have been extensively explored in the budding yeast <i>Saccharomyces cerevisiae</i>, little is known about how this coping response is regulated in the evolutionary distant fission yeast <i>Schizosaccharomyces pombe</i>. Here, we show that <i>S. pombe</i> autophagy in response to glucose limitation relies on mitochondrial respiration and the electron transport chain (ETC), but, in contrast to <i>S. cerevisiae</i>, the AMP-activated protein kinase (AMPK) and DNA damage response pathway components do not modulate fission yeast autophagic flux under these conditions. In the presence of glucose, the cAMP-protein kinase A (PKA) signaling pathway constitutively represses <i>S. pombe</i> autophagy by downregulating the transcription factor Rst2, which promotes the expression of respiratory genes required for autophagy induction under limited glucose availability. Furthermore, the stress-activated protein kinase (SAPK) signaling pathway, and its central mitogen-activated protein kinase (MAPK) Sty1, positively modulate autophagy upon glucose limitation at the transcriptional level through its downstream effector Atf1 and by direct <i>in vivo</i> phosphorylation of Rst2 at S292. Thus, our data indicate that the signaling pathways that govern autophagy during glucose shortage or starvation have evolved differently in <i>S. pombe</i> and uncover the existence of sophisticated and multifaceted mechanisms that control this self-preservation and survival response.

巨自噬/自噬（Macroautophagy/autophagy）是真核生物在营养饥饿条件下触发的关键适应性生理应答，葡萄糖是多数细胞最主要的即时碳源与能量来源。尽管在出芽酵母酿酒酵母（Saccharomyces cerevisiae）中，葡萄糖饥饿诱导自噬的分子机制已得到广泛研究，但在进化亲缘关系较远的裂殖酵母粟酒裂殖酵母（Schizosaccharomyces pombe）中，人们对该应激应答的调控机制仍知之甚少。本研究发现，粟酒裂殖酵母应对葡萄糖限制的自噬依赖于线粒体呼吸与电子传递链（ETC）；但与酿酒酵母不同的是，AMP激活的蛋白激酶（AMPK）与DNA损伤应答通路（DNA damage response pathway）组分在该条件下并不会调控裂殖酵母的自噬流。在葡萄糖存在的情况下，环腺苷酸（cAMP）-蛋白激酶A（PKA）信号通路通过下调转录因子Rst2，组成型抑制粟酒裂殖酵母的自噬，而Rst2可在葡萄糖有限的条件下促进自噬诱导所需的呼吸基因表达。此外，应激激活的蛋白激酶（SAPK）信号通路及其核心丝裂原激活的蛋白激酶（MAPK）Sty1，可通过下游效应因子Atf1，并通过直接在体内（in vivo）磷酸化Rst2的S292位点，在转录水平上正向调控葡萄糖限制条件下的自噬。综上，本研究数据表明，调控葡萄糖匮乏或饥饿条件下自噬的信号通路在粟酒裂殖酵母与酿酒酵母中存在演化差异，并揭示了控制这一自我保护与存活应答的复杂多层面调控机制。