Is nuclear sirtuin SIRT6 a master regulator of immune function?

Abstract

The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes. Cells utilize diverse fuel sources and switch back and forth between different metabolic pathways depending on their energy needs. The three most critical metabolic pathways on which immune cells depend to meet their energy needs are oxidative metabolism, glycolysis, and glutaminolysis. Dynamic switching between these metabolic pathways is needed for optimal function of the immune cells. Moreover, switching between these metabolic pathways needs to be tightly regulated to achieve the best results. Immune cells depend on the Warburg effect for their growth, proliferation, secretory, and effector functions. Here, we hypothesize that the sirtuin, SIRT6, could be a negative regulator of the Warburg effect. We also postulate that SIRT6 could act as a master regulator of immune cell metabolism and function by regulating critical signaling pathways.

SIRT6 Widely Regulates Aging, Immunity, and Cancer

“…Although few studies have shown SIRT6 to affect immune cell function through directly regulating immunometabolism, SIRT6 has been found to regulate immune cell activity via effects on PI3K/Akt, NF-κB, and HIF-1α as discussed above. The above three signaling pathways could be involved in regulation of the TCA cycle, glycolysis, pentose phosphate pathway, and Warburg effect, thereby affecting the energy metabolism of immune cells in the resting state and activated state ( 72 , 89 – 94 ). SIRT6 also regulates intracellular levels of NAD + , which is an electron acceptor with a key role in cell metabolism.…”

“…Therefore, SIRT6 is likely to regulate immune cell proliferation, growth, and function by affecting immunometabolism. Pillai’s review discusses this point in detail and proposes that SIRT6 participates in short-term regulation of immune cells through PTMs and long-term regulation through transcriptional regulation of metabolism-related genes ( 89 ). Therefore, how SIRT6 regulates immunometabolism and how this regulation affects cell function will be an interesting research direction.…”

Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies

“…SIRT6 is a nuclear SIRT isoform that interacts with chromatin and finely regulates genome maintenance, response to oxidative stress, inflammation, senescence, and metabolism. Constant exposure to oxidative stress has been demonstrated to lead to the onset of a senescence phenotype [ 97 ]. This phenotype consists of a reduction of cell growth and proliferation, along with higher expression of the senescence-associated β-galactosidase.…”

Acetylation in Tumor Immune Evasion Regulation

“…High Sirt6 expression levels are observed in the immune system. It may be a possibly a negative regulator of immune cell function and metabolism, which related to neutrophil inactivation and increased the polarization to M2 macrophages ( Pillai and Gupta, 2021 ).…”