Does mTORC1 inhibit autophagy?

mTORC1 tightly regulates autophagy by suppressing autophagy induction via phosphorylation-dependent inhibition of ULK1/2 and the VPS34 complex and by preventing global expression of lysosomal and autophagy genes through TFEB phosphorylation.

What is the relationship between mTOR and autophagy?

As outlined above, mTOR promotes anabolic cellular processes leading to growth. This is further facilitated by the suppression of protein catabolism, most notably autophagy. Autophagy is a basic catabolic process in the cell that degrades damaged organelles or dysfunctional proteins to gain energy or free amino acids.

Does mTOR increase autophagy?

We observed that mTOR inhibition led to an increase in cell viability and was accompanied by an increase in autophagic activity. It was also shown that autophagy was activated under conditions of severe ER stress but that in the latter phase of stress it was inhibited at the time of apoptosis activation.

What diseases are caused by autophagy?

Deregulated autophagy at different steps of the pathway, whether excessive or downregulated, has been proposed to be associated with neurodegenerative disorders such as Alzheimer’s-, Huntington’s-, and Parkinson’s-disease, known for their intracellular accumulation of protein aggregates.

Does mTORC1 inhibit autophagy at dual stages?

Since mTORC1 is a well-known inhibitor of autophagy, albeit in the initial stages of autophagy during autophagosome formation, an unexplored inhibitory mechanism that intervenes with lysosomal fusion with autophagosome at the perinuclear region by mTORC1 may exist.

What happens when mTOR is activated?

Activation of mTOR complex 1 (mTORC1) is triggered by oxidative stress, amino-acid levels and endosomal traffic to the lysosome by small GTPases such as Rab4A. In turn, mTORC1 promotes inflammation by skewing T-cell development.

What is autophagy in pathology?

Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis. Autophagy principally serves an adaptive role to protect organisms against diverse pathologies, including infections, cancer, neurodegeneration, aging, and heart disease.

How important is autophagy?

As an essential process to maintain cellular homeostasis and functions, autophagy is responsible for the lysosome-mediated degradation of damaged proteins and organelles, and thus misregulation of autophagy can result in a variety of pathological conditions in human beings.

What is the mTORC1 pathway and why is it important?

Aberrant mTORC1 signaling is also implicated in aging, cancers, obesity, and Alzheimer’s amongst others 16. Therefore, deciphering the molecular regulators of autophagy and the mTORC1 pathway has significant ramifications for the fundamental cellular aging process and the etiology of autophagy-related disorders.

How does cib2 affect mTORC1 signaling?

In our model, CIB2 is critical for regulating mTORC1 signaling and autophagy in RPE via its preferential interaction with nucleotide empty or GDP-Rheb (inactive form) and raptor. Loss of CIB2 results in reduced autophagy and exacerbated mTORC1 signaling, thus leading to RPE pathology and secondary photoreceptor (PR) dysfunction.

Is mTORC1 signaling dysregulated in dry AMD?

Fig. 9: mTORC1 signaling and CIB2 levels are dysregulated in RPE/choroid lysates from dry AMD cases, while over-expressing CIB2 downregulates mTORC1 signaling in cell lines. Fig. 10: PR function but not RPE pathology can be rescued by exogenous retinoid. Strauss, O.

What is the role of RHEB in the activation of mTORC1?

GTP-loaded active Rheb allosterically realigns the kinase active site of mTORC1, and thus is a potent and obligate activator of mTORC1 on the surface of the lysosomes 15. We found that CIB2 preferentially binds to, in order of binding strength, the nucleotide-empty form of Rheb followed by GDP-loaded inactive Rheb, and then GTP-loaded active Rheb.