Sirtuins, possessing either histone deacetylase or mono-ribosyltransferase activity, regulate important pathways in bacteria, archaea and eukaryotes. SIRT6, an enzyme highly expressed in skeletal muscles, brain, heart, liver, and thymus, affects transcriptional regulation in a tissue-specific manner. This enzyme has a two-domain structure that consists of a large Rossmann fold and a smaller and structurally more varied sequence containing a Zn(2+)-binding motif. The C-terminus is required for proper nuclear localization, while the N-terminus is important for chromatin association and for intrinsic catalytic activity. SIRT6 promotes resistance to DNA damage and oxidative stress, the principal defects associated with age-related diseases. The modulation of aging and other metabolic functions by SIRT6 may be indicative of previously unrecognized regulatory systems in the cell. The propensity of individual SIRT6 molecules to undergo intramolecular mono-ADP-ribosylation, suggests this auto-ribosylation may contribute to the self-regulation of SIRT6 function. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. It was known that, similar to the yeast Sir2 protein, human SIRT6 deacetylates histones and regulates DNA stability and repair; however, new mechanistic insights can be derived from the discovery of the highly substrate-specific histone deacetylase activity of SIRT6. This deacetylase activity promotes proper chromatin function in several physiologic contexts, to include telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 may help prevent cellular senescence. Moreover, successful molecular modulation of SIRT6 activity may lead to the development of new chemotherapeutic modalities. The action of SIRT6 is described in this review, with an emphasis on the cellular roles of the enzyme and the relation of those enzymatic functions to human biology and disease.
Members of the mammalian inflammatory caspase family, including caspase‐1, caspase‐4, caspase‐5, caspase‐11, and caspase‐12, are key regulators of the innate immune response. Most studies to date have focused on the role of caspase‐1 in the maturation of the proinflammatory cytokine interleukin‐1β and its upstream regulation by the inflammasome signaling complexes. However, an emerging body of research has supported a role for caspase‐4, caspase‐5, and caspase‐11 in both regulating caspase‐1 activation and inducing the inflammatory form of cell death called pyroptosis. This inflammatory caspase pathway appears essential for the regulation of cytokine processing. Consequently, insight into this noncanonical pathway may reveal important and, to date, understudied targets for the treatment of autoinflammatory disorders where the inflammasome pathway is dysregulated. Here, we will discuss the mechanisms of inflammasome and inflammatory caspase activation and how these pathways intersect to promote pathogen clearance.
Excessive release of heme from RBCs is a key pathophysiological feature of several disease states, including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and the endothelium. In this study, we show that extracellular heme engages the human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1β. Heme-induced IL-1β release was further increased in macrophages from patients with sickle cell disease. In human primary macrophages, heme activated caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 was independent of canonical inflammasomes. Furthermore, we show that both caspase-4 and caspase-5 are essential for heme-induced IL-1β release, whereas caspase-4 is the primary contributor to heme-induced cell death. Together, we have identified that extracellular heme is a damage-associated molecular pattern that can engage canonical and noncanonical inflammasome activation as a key mediator of inflammation in macrophages.
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