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Message:

> Complex regulation:
> 
> https://medicalxpress.com/news/2024-06-scientists-decades-mystery-nlrc5-sensor.html
> 
> 
> "One of the key innate immune strategies to respond to threats is through cell death. New research from St. Jude Children's Research Hospital discovered that NLRC5 plays a previously unknown role as an innate immune sensor, triggering cell death. The findings, published in Cell, show how NLRC5 drives PANoptosis, a prominent type of inflammatory cell death. This understanding has implications for the development of therapeutics that target NLRC5 for the treatment of infections, inflammatory diseases and aging.
> 
> ***
> 
> "Nucleotide-binding oligomerization domain-like receptors (NLRs) are a large family of important molecules involved in inflammatory signaling. They are generally thought to function as innate immune sensors that detect threats. However, the specific roles of several NLRs in sensing are not yet understood. Scientists at St. Jude conducted a large screen, testing a specific NLR, NLRC5, to see what threats activate it. Through their efforts, they discovered that depletion of nicotinamide adenine dinucleotide (NAD), a molecule essential in energy production, triggers NLRC5-mediated cell death through PANoptosis.
> 
> ***
> '
> "Among all the combinations we tested, we identified that the combination of heme plus PAMPs or cytokines specifically induces NLRC5-dependent inflammatory cell death, PANoptosis," said co-first author Balamurugan Sundaram, Ph.D., St. Jude Department of Immunology. "Our results showed for the first time that NLRC5 is central to responses to hemolysis, which can occur during infections, inflammatory diseases and cancers."
> 
> "Upon identifying the heme-containing PAMP, DAMP and cytokine combinations that trigger NLRC5-dependent inflammatory cell death, the researchers further investigated how NLRC5 is regulated. They found that NAD levels drive NLRC5 protein expression. If NAD is depleted, that sounds an alarm that there is a threat the immune system should recognize. The researchers found that depletion of NAD is sensed by NLRC5, triggering PANoptosis.
> 
> "'By supplementing with the NAD precursor, nicotinamide, we reduced NLRC5 protein expression and PANoptosis," said co-first author Nagakannan Pandian, Ph.D., St. Jude Department of Immunology. "Therapeutically, nicotinamide has been widely studied as a nutrient supplement, and our findings suggest it could be helpful in treating inflammatory diseases."
> 
> "The researchers also discovered that NLRC5 is in an NLR network with NLRP12, which come together with other cell death molecules and form an NLRC5-PANoptosome complex that triggers inflammatory cell death. The finding builds on previous research by the Kanneganti lab showcasing the role of NLRP12 in PANoptosis."
> 
> Comment:  cell death is so important it needs these complex steps of control. This was designed, not by chance.