Nuclear factor κB (NF-κB) regulator NLRC5 has recently been identified as a key player in the cellular response to NAD+ depletion, which can occur due to various stressors including metabolic imbalances and oxidative stress. NAD+ is a critical coenzyme involved in redox reactions essential for energy metabolism, DNA repair, and cell signaling. Depletion of this molecule triggers complex intracellular events to restore homeostasis, among them the formation of macromolecular complexes known as PANoptosomes.
PANoptosis is a unique form of programmed cell death that combines features of pyroptosis, apoptosis, and necroptosis. The formation of a PANoptosome marks the activation of this intricate cell death pathway. In response to NAD+ deficiency, NLRC5 has been shown to recruit several essential components including RIPK1, RIPK3, caspase-8, and ASC (apoptosis-associated speck-like protein containing a CARD), leading to the assembly of the PANoptosome complex.
Once formed, the PANoptosome initiates downstream signaling cascades that result in cell death and inflammation. The activation of caspases within the complex leads to pyroptotic and apoptotic death mechanisms characterized by cell lysis and DNA fragmentation respectively. Concomitantly, the necrosome component RIPK3 mediates necroptosis hallmarks such as membrane rupture.
Inflammation is a crucial secondary consequence driven by the release of damage-associated molecular patterns (DAMPs) from cells undergoing PANoptosis. These DAMPs activate immune responses aimed at managing cellular damage or pathogen invasion but can also perpetuate inflammatory diseases if uncontrolled. Elevated levels of pro-inflammatory cytokines like IL-1β, IL-18, TNF-α, and IFN-γ have been observed in conditions associated with persistent NAD+ depletion.
Understanding the exact role of NLRC5 in sensing NAD+ levels and orchestrating PANoptosis opens new avenues for therapeutic interventions. Targeting NLRC5-mediated pathways could potentially mitigate inflammatory responses and regulate cell death in conditions characterized by metabolic stress or chronic inflammation.
In conclusion, NLRC5 plays a pivotal role as a cellular sensor for NAD+ depletion. By facilitating PANoptosome formation and driving PANoptosis along with inflammatory responses, it fulfills a critical function in maintaining cellular homeostasis under stress conditions. Further research into this pathway promises potential breakthroughs in treating inflammation-linked disorders and enhancing overall cellular resilience against metabolic disturbances.
