Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis

Song, Jia; Zhang, Xin; Yin, Yuyao; Guo, Ming; Zhao, Xuyang; Wang, Likun; Ren, Caixia; Yin, Yuxin; Zhang, Xuehui; Deng, Xuliang; Lü, Dan

doi:10.1002/advs.202206344

Cited by 7 publications

(1 citation statement)

References 43 publications

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“…DAI binds to several types of cytoplasmic DNA to activate IFNs production via the TBK1–IRF3 axis, which makes it necessary for the response of endogenous aberrant DNA [ 138 ]. Significantly, a recent study showed that ZBP-1-RIPK3 signaling that caused T cell necroptosis is stimulated by knocking down RPA1, suggesting that ZBP-1 may function as a positive sensor for DNA damage [ 139 ]. Retinal pigment epithelial cells consistently expressed significant levels of ZBP-1 in response to oxidative stress-induced mtDNA accumulation [ 140 ].…”

Section: The Regulation Of Innate Immune Sensors By Ddr Componentsmentioning

confidence: 99%

When DNA-damage responses meet innate and adaptive immunity

Tong,

Song,

Zhang

et al. 2024

Cell. Mol. Life Sci.

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When cells proliferate, stress on DNA replication or exposure to endogenous or external insults frequently results in DNA damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms to prevent DNA damage. Depending on the type of broken DNA, the various pathways, Base-Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair pathways, can be activated separately or in combination to repair DNA damage. To preserve homeostasis, innate and adaptive immune responses are effective defenses against endogenous mutation or invasion by external pathogens. It is interesting to note that new research keeps showing how closely DDR components and the immune system are related. DDR and immunological response are linked by immune effectors such as the cyclic GMP-AMP synthase (cGAS)–Stimulator of Interferon Genes (STING) pathway. These effectors act as sensors of DNA damage-caused immune response. Furthermore, DDR components themselves function in immune responses to trigger the generation of inflammatory cytokines in a cascade or even trigger programmed cell death. Defective DDR components are known to disrupt genomic stability and compromise immunological responses, aggravating immune imbalance and leading to serious diseases such as cancer and autoimmune disorders. This study examines the most recent developments in the interaction between DDR elements and immunological responses. The DDR network’s immune modulators’ dual roles may offer new perspectives on treating infectious disorders linked to DNA damage, including cancer, and on the development of target immunotherapy.

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Section: The Regulation Of Innate Immune Sensors By Ddr Componentsmentioning

confidence: 99%

When DNA-damage responses meet innate and adaptive immunity

Tong,

Song,

Zhang

et al. 2024

Cell. Mol. Life Sci.

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Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis

et al. 2023

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The peripheral T cell pool is maintained at dynamic homeostasis through fine-tuning of thymic output and self-renewal of naïve T cells. Lymphopenia or reduced lymphocyte number is implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, it is reported that the replication protein A1 (RPA1) plays a critical role in T cell homeostasis. Utilizing T cell-specificRpa1-deficient (Rpa1 fl/fl Cd4-cre) mice, loss of Rpa1 results in lymphopenia through restraining peripheral T cell population and limiting TCR repertoire diversity. Moreover, Rpa1 fl/fl Cd4-cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Clinical analysis reveals that the expression of RPA1 is reduced in patients with ulcerative colitis or other autoinflammatory diseases. Mechanistically, depletion of RPA1 activates ZBP1-RIPK3 signaling through triggering the genomic DNA leakage into cytosol, consequently resulting in T cell necroptosis. This necroptotic T cell death induced by RPA1 deficiency allows the release of damage-associated molecular patterns (DAMPs), which in turn recruits leukocytes and exacerbates inflammatory response. Reciprocally, chemical or genetic inhibition of necroptosis signaling can ameliorate the Rpa1 deficiency-induced inflammatory damage. The studies thus uncover the importance of RPA1-ZBP1-RIPK3 axis in T cell homeostasis and provide a promising strategy for autoinflammatory disease treatment.

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The Deubiquitinase OTUD1 Suppresses Secretory Neutrophil Polarization And Ameliorates Immunopathology of Periodontitis

Song,

Zhang,

Bai

et al. 2023

Advanced Science

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Tissue‐infiltrating neutrophils (TINs) secrete various signaling molecules to establish paracrine communication within the inflammatory milieu. It is imperative to identify molecular mediators that control this secretory phenotype of TINs. The present study uncovers a secretory neutrophil subset that exhibits increased pro‐inflammatory cytokine production and enhanced migratory capacity which is highly related with periodontal pathogenesis. Further analysis identifies the OTU domain‐containing protein 1 (OTUD1) plays a regulatory role in this secretory neutrophil polarization. In human and mouse periodontitis, the waning of inflammation is correlated with OTUD1 upregulation, whereas severe periodontitis is induced when neutrophil‐intrinsic OTUD1 is depleted. Mechanistically, OTUD1 interacts with SEC23B, a component of the coat protein II complex (COPII). By removing the K63‐linked polyubiquitin chains on SEC23B Lysine 81, the deubiquitinase OTUD1 negatively regulates the COPII secretory machinery and limits protein ER‐to‐Golgi trafficking, thus restricting the surface expression of integrin‐regulated proteins, CD9 and CD47. Accordingly, blockade of protein transport by Brefeldin A (BFA) curbs recruitment of Otud1‐deficient TINs and attenuates inflammation‐induced alveolar bone destruction. The results thus identify OTUD1 signaling as a negative feedback loop that limits the polarization of neutrophils with secretory phenotype and highlight the potential application of BFA in the treatment of periodontal inflammation.

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Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis

Cited by 7 publications

References 43 publications

When DNA-damage responses meet innate and adaptive immunity

When DNA-damage responses meet innate and adaptive immunity

Loss of RPA1 Impairs Peripheral T Cell Homeostasis and Exacerbates Inflammatory Damage through Triggering T Cell Necroptosis

The Deubiquitinase OTUD1 Suppresses Secretory Neutrophil Polarization And Ameliorates Immunopathology of Periodontitis

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