Lysosomal mTORC2/PHLPP1/Akt axis: a new point of control of chaperone-mediated autophagy

Chaperone-mediated autophagy (CMA), a mechanism for degradation of cytosolic proteins in lysosomes, is one of the most selective types of autophagy in mammals [1]. Identification and degradation of single proteins via CMA allows precise remodeling of the cellular proteome and removal of altered proteins. These characteristics explain the contribution of CMA to the cellular response to stress, in cellular quality control and in the fine-tune regulation of processes such as cellular metabolism, differentiation and reprograming [1]. The molecular components that participate in substrate targeting and translocation across the lysosomal membrane in CMA are well characterized [1]. In contrast, the signaling mechanisms that contribute to its regulation were poorly understood. Until recently only signaling through the retinoic acid receptor α had been identified to negatively regulate CMA activity [2]. In T cells, nuclear factor of activated T-cells (NFAT) signaling mediates the upregulation of CMA required for T cell activation, but it remains unknown whether or not this regulation is T cell specific [3]. Despite the unique functions attributed to CMA, this pathway does not act in isolation. Quite on the contrary, growing evidence supports coordinated functioning of the different autophagic pathways that co-exist in the cell and direct cross-talk between macroautophagy and CMA (both maximally activated in response to stress). Thus, CMA-defective cells maintain protein degradation at normal levels through macroautophagy up-regulation [1]. Similarly, blockage of macroautophagy results in activation of CMA even under basal conditions [1]. Although these pathways are not redundant and the deficit of the blocked pathway becomes evident upon stress, this partial compensation serves to maintain cellular homeostasis under basal conditions. Consequently, understanding the basis of this bi-directional cross-talk between macroautophagy and CMA becomes important, especially in pathological conditions with blockage of one of these autophagic pathways. In our search for signaling mechanisms that regulate CMA and that could also participate in the autophagic crosstalk, we focused our attention on the mammalian target of rapamycin (mTOR), a serine/ threonine kinase that serves as one of the main cellular nutritional sensors. mTOR senses and integrates different nutritional inputs, including growth factors, energy levels, cellular stress, and amino acids. mTOR is present in two distinct complexes, mTORC1 and mTORC2. There is extensive evidence of a tight relation of mTORC1 with lysosomes and macroautophagy regulation. Amino acids signal to mTORC1, and allow its translocation to the lysosomal surface where it becomes activated. This process is mediated by the coordinated actions of multiple complexes, including the Ragulator, and Rag GTPases [4]. Activation of lysosomal mTORC1 results in macroautophagy inhibition. Interestingly, we have recently identified that mTOR is also involved in CMA regulation [5] Figure 1. CMA is under the negative regulation of mTORC2 and its Editorial