Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development

Abstract

Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.

OMA1 High-Throughput Screen Reveals Protease Activation by Kinase Inhibitors

“…However, just two of the 10 drugs led to distinct OPA1 and Luke-S1 cleavage in Western blotsand only after 3 h of 50 μM, which would speak for the latter. AMPK and GSK3B could be potential mediators in such signaling events. , OPA1 has also been connected to NF-κB signaling . OMA1’s cancer connection has been recognized previously.…”

“…The capacity of this electromotive force increases when the inner membranes align in orderly stacks, which are reinforced by the structural protein OPA1. − This is illustrated by the parallel alignment of the cristae, for instance, in cardiomyocytes, which have been shown to rely on OPA1. − These membrane stacks are rearrangedand OPA1 reorganizedin cells switching from the efficient generation of ATP to the resourceful synthesis of metabolites needed for cell growth and proliferation. , Examples for this include the fragmented appearance of mitochondria in activated immune cells, pluripotent stem cells and in cancer cells. − It is still unclear, however, how the morphological changes of the inner membrane in response to energy-metabolic demands are regulated. It was suggested the i-AAA protease is downstream of AMPK . Another report suggested OMA1 is downstream of GSK3B …”

Sirtuin 5 is Dispensable for CD8+ T Cell Effector and Memory Differentiation

“…During caloric restriction, SIRT3 modulated amino acid catabolism and β-oxidation by regulating ornithine transcarbamoylase activity and urea cycle ( Hallows et al, 2011 ). Glucose limitation activated AMPK and its subsequent SENP1-SIRT3 signaling, promoting OXPHOS and mitochondrial fusion, which was beneficial to the anti-tumor immunity of T cells ( He et al, 2021 ). Therefore, it remains unclear whether SIRT5 may play an important role under other physiological or pathological conditions, such as long time HFD, fasting, hypoxia, low glucose, low glutamine, or the tumor microenvironment.…”

Directing T-Cell Immune Responses for Cancer Vaccination and Immunotherapy

“…AMPK controls cellular growth through inhibition of mTOR [243], specifically inhibiting mTORC1 signalling in part by phosphorylating mTORC1 subunit Raptor [244] and promoting OXPHOS. AMPK can induce mitochondrial remodelling via the activation of Sirtuin (SIRT)-3 leading to Optic Atrophy (Opa)-1 dependent mitochondrial remodelling [245]. AMPK also activates peroxisome proliferator-activated coactivator 1α (PGC1α), the master regulator of mitochondrial biogenesis and function, by regulating the intracellular levels of NAD+, required as a substrate for the deacetylase Sirt1, which is involved in mitochondrial biogenesis, switching on oxidative phosphorylation [246], vital to the generation of effective anti-tumour immunity in the TME [241].…”