PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS‐STING‐Mediated Interferon Response

Abstract

The Plk1‐interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency‐induced embryonic lethality in mice. However, the function of PICH that is required to suppress embryonic lethality in PICH‐deficient mammals remains to be determined. Previous clinical studies suggest a link between PICH deficiency and the onset of acquired aplastic anemia. Here, using Pich knock‐out (KO) mouse models, the authors provide evidence for a mechanistic link between PICH deficiency and defective hematopoiesis. Fetal livers from Pich‐KO embryos exhibit a significantly elevated number of hematopoietic stem cells (HSCs); however, these HSCs display a higher level of apoptosis and a much‐reduced ability to reconstitute a functional hematopoietic system when transplanted into lethally irradiated recipients. Moreover, these HSCs show an elevated cytoplasmic dsDNA expression and an activation of the cGAS‐STING pathway, resulting in excessive production of type I interferons (IFN). Importantly, deletion of Ifnar1 or cGAS reverses the defective hematopoiesis. The authors conclude that loss of PICH results in defective hematopoiesis via cGAS‐STING‐mediated type I IFN production.

Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS‐STING Activation

“…Such dsDNA is likely to be generated from the damaged bridge DNA. [ 37 ] We conclude that the extensive formation of chromatin bridges induces both the formation of micronuclei and cytosolic dsDNA in the absence of ANKLE1‐mediated bridge processing, leading to the activation of cGAS‐STING pathway.…”

Somatic gene mutations expose cytoplasmic DNA to co-opt the cGAS/STING/NLRP3 axis in myelodysplastic syndromes

“…Type I IFNs block maturation of HSPCs, a process that is attenuated by inhibition of the cytosolic DNA sensor cGAS ( 14 ). Given the increased prevalence of micronuclei that may expose genomic DNA through porous nuclear membranes and accumulation of cytosolic R-loops in our murine models and primary specimens, we next examined whether cGAS engages these sources of cytoplasmic DNA.…”

“…Type I interferons block maturation of HSPCs, a process that is attenuated by inhibition of the cytosolic DNA sensor, cGAS. (14) Given the increased prevalence of micronuclei that may expose genomic DNA through porous nuclear membranes, and accumulation of cytosolic R-loops in our murine models and primary specimens, we next examined whether cGAS engages these sources of cytoplasmic DNA. We first used immunofluorescence staining to demonstrate cGAS colocalization with both micronuclei (Figure 2A) and cytoplasmic R-loops (Figure 2B) and indeed found that cGAS interacted with both in MDS BM-MNCs as well as the murine mutation variants.…”

“…cGAS and stimulator of IFN genes (STING) form a cell-intrinsic DNA surveillance pathway that recognizes cytosolic DNA, leading to ISG transcription and NLRP3 inflammasome activation ( 12 , 13 ). Further, recent data demonstrate that cGAS-induced ISG expression is responsible for defective hematopoiesis in in vivo models ( 14 ). cGAS dimerizes upon dsDNA engagement, catalyzing generation of 2′,3′-cyclic GMP-AMP (cGAMP) that binds to and activates STING ( 12 ).…”

Enhanced Immunotherapy Based on Combining the Pro-phagocytosis and Anti-phagocytosis Checkpoint Blockade for Tumor Eradication

“…HMGB1 could promote the activation of DCs to phagocytose apoptotic tumor cells, bind toll-like receptor 4 (TLR4) to facilitate DC maturation, and enhance antigen presentation to cytotoxic T lymphocytes (CTLs) . While ATP could stimulate the infiltration of CTLs in the tumor microenvironment, chemotherapeutic drug-induced damage of DNA could also enhance cGAS-STING-mediated type I interferon (IFN) response to activate anti-tumor immune responses. , At the same time, ICD could enhance the translocation of CRT molecules, an “eat me” pro-phagocytosis signal that interacts with the low-density lipoprotein receptor-related protein 1 (LRP1), facilitating its recognition by professional antigen-presenting cells (APCs) and acting as a critical molecular component in promoting ICD to the plasma membrane of tumor cells, which could induce tumor-associated macrophages (M2 phenotype) to transform into a phenotype with antitumor activity (M1 phenotype). , Hence, not only will the strategy that combines the CD47 blockade with chemotherapy-induced ICD significantly improve anticancer therapeutic efficacy but also considerably increase the beneficiary population of immunotherapy.…”