Let-7 Coordinately Suppresses Components of the Amino Acid Sensing Pathway to Repress mTORC1 and Induce Autophagy

Abstract

SUMMARY Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway – the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 microRNA as capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain to eliminate protein aggregates, establishing its physiological relevance for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms.

Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

“…However, because LIN28, MYC, and RAS could activate various downstream events, it is possible that these genes affect the immunoregulatory property of MSCs indirectly. Furthermore, let-7 could suppress components of the amino acid sensing pathway (Map4k3, RagC, and RagD) to induce autophagy, 49 which are crucial for therapeutic potential of MSC in autoimmune diseases. 50 Therefore, we could not exclude the possibility that let-7a functions through other targets.…”

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…Let-7f has been reported to repress the glutamine transporter ASCT2 (Slc1a5), suppressing the mTORC1 pathway and inducing autophagy in neurons (Dubinsky et al, 2014). The high-affinity glutamine transporter Slc1a5 is rapidly elevated at both the mRNA and protein levels following lymphocyte stimulation (Nakaya et al, 2014).…”

“…Studies using various mouse models of cancer indicate that let-7 usually inhibits tumor growth in adult mice (Esquela-Kerscher et al, 2008;Hu et al, 2013;Wu et al, 2015). A handful of previous studies have also implicated let-7 in the regulation of glucose metabolism and amino acid sensing (Boyerinas et al, 2010;Dubinsky et al, 2014;Jiang and Baltimore, 2016;Nguyen and Zhu, 2015;Zhu et al, 2011). However, relatively little is known about the physiological role of a single let-7 cluster in the adaptive immune system, for instance in the regulation of in vivo B cell function.…”

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…Intriguingly, while let-7-Lin28-mediated metabolic reprogramming induces a regenerative response in other mammalian organs [135,136], let-7 is capable of directly promoting neuronal autophagy in mice, a regulatory potential that, the authors suggest, could be extended to other tissues [137].…”