Sirtuin 6–Myc proto-oncogene protein–glutaminolysis–mechanistic target of rapamycin complex 1 axis (SIRT6-c-Myc-mTORC1)

The SIRT6–c-Myc–glutaminolysis–mTORC1 axis is a critical regulatory pathway that maintains the quiescent state of naïve CD4+ T cells. Sirtuin 6 (SIRT6) functions as a metabolic gatekeeper by deacetylating histone H3 at lysine 9 (H3K9) and lysine 56 (H3K56) at the promoters of glycolytic and glutaminolytic genes, specifically suppressing the transcription factor c-Myc (Zhang et al., 2020). In the absence of SIRT6, elevated c-Myc levels drive increased glutaminolysis, which in turn provides the signals necessary to activate the mechanistic target of rapamycin complex 1 (mTORC1). This activation leads to the loss of T cell quiescence, promoting premature activation, proliferation, and effector differentiation. Dysregulation of this axis is implicated in inflammatory and autoimmune disorders, as well as age-related immune decline. Targeting components of this axis, such as activating SIRT6 or inhibiting mTORC1, offers potential therapeutic strategies for modulating immune responses and treating metabolic-related immune pathologies. Research indicates that SIRT6 deficiency in T cells leads to a systemic inflammatory phenotype due to the spontaneous activation of CD4+ T cells (Zhang et al., 2020). Pharmacological modulation of this axis could potentially restore immune homeostasis in conditions characterized by chronic inflammation or immunosenescence.

Other names

SIRT6-c-Myc-glutaminolysis-mTORC1 pathwaySirtuin 6-mediated metabolic reprogramming axisSIRT6-c-Myc-mTORC1 axis in naïve CD4+ T cells

SIRT6 acts as a histone deacetylase that suppresses c-Myc expression by deacetylating H3K9 and H3K56 at its promoter; the resulting inhibition of c-Myc reduces glutaminolysis, which prevents the activation of mTORC1 and maintains T cell quiescence (Zhang et al., 2020).