Calcitriol Prevents RAD51 Loss and cGAS‐STING‐IFN Response Triggered by Progerin

Abstract

Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced “progerin” has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin‐induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease‐mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1‐regulated interferon (IFN)‐like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin‐expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated‐RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin‐expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

“…Although an increase rate of cathelcidin has been postulated to be one of the mechanisms through which vitamin-D could better control SARS-CoV2 initial infection, vitamin-D might also prevent the delayed over-reaction of the immune system (Figure). Indeed, in prematurely senescent cells, calcitriol (1,25-(OH) 2 D 3 ) represses the cGAS/STING/IFN cascade induced by exposure of chromatin self-DNA in the cytosol [37].…”

“…STING can contribute to Kawasaki disease, an innate overimmune response disorder following viral insults, in several ways. The mainstays of Kawasaki disease treatment, IVIgs and aspirin, both inhibit the STING pathway [ 38 , 39 ], which is also down-regulated by Vitamin-D [ 37 ]. Excessive triggering of the STING pathway can also lead to pyroptosis of monocyte-macrophages, and release of the highly prothrombotic tissue factor [ 54–57 ], also found in excess in lung tissues of severe COVID-19 patients [ 49 ].…”

“…STING can contribute to Kawasaki disease, an innate overimmune response disorder following viral insults, in several ways. The mainstays of Kawasaki disease treatment, IVIgs and aspirin, both inhibit the STING pathway [ 38 , 39 ], which is also down-regulated by Vitamin-D [ 37 ].…”

cGAS/STING: novel perspectives of the classic pathway

“…And genomic instability caused by the activation of multipolar mitotic spindles [50], the production of DNA-damage agents [51], centrosome abnormalities [52], telomeres dysfunctions [53][54][55] andp53/p21 mutation [56] are hallmarks of cancer and cellular senescence. The disruption of the micronuclei caused by aberrant accumulation of the endosomal sorting complex required for transport-III (ESCRT-III) complex or the mutant prelamin A (progerin) accentuates DNA damage and enhances proinflammatory responses via cGAS/STING pathway [57][58][59]. The formation of micronuclei has a dual function.…”

Le vieillissement

“…Les perturbations de l'architecture nucléaire et du réseau de lamines pourraient donc activer des signaux capables de faire rentrer les cellules en sénescence, nécessaire à la protection et au redémarrage des fourches de réplication. Le stress réplicatif mène à la production de cytokines inflammatoires et d'interférons via la voie cGAS-STING [49]. Des modèles murins d'accumulation de la prélamine A farnésylée présentent aussi une inflammation accrue dépendante de NF-kB [50].…”