bims-iorami 2024-02-25 papers

Issue of 2024–02–25
six papers selected by
Chenxiao Yu, Soochow University

JCI Insight. 2024 Feb 20. pii: e168824. [Epub ahead of print]

Potentiating the radiation-induced type I interferon anti-tumoral immune response by ATM inhibition in pancreatic cancer.

Qiang Zhang, Long Jiang, Weiwei Wang, Amanda K Huber, Victoria M Valvo, Kassidy M Jungles, Erin A Holcomb, Ashley N Pearson, Stephanie The, Zhuwen Wang, Leslie A Parsels, Joshua D Parsels, Daniel R Wahl, Arvind Rao, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan.

Radiotherapy induces a Type I interferon (T1IFN)-mediated anti-tumoral immune response that we hypothesized could be potentiated by a first-in-class ATM inhibitor leading to enhanced innate immune signaling, T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound AZD0156 on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced anti-tumoral immune responses and sensitized to anti-PD-L1, producing immunogenic memory and durable tumor control. Therapeutic responses were associated with increased intratumoral CD8+ T cell frequency and effector function. Tumor control was dependent on CD8+ T cells as therapeutic efficacy was blunted in CD8+ T cell-depleted mice. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN leading to both innate and subsequent adaptive anti-tumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy.

Keywords: DNA repair; Innate immunity; Oncology; Radiation therapy

DOI: https://doi.org/10.1172/jci.insight.168824

Nat Commun. 2024 Feb 20. 15(1): 1534

Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.

Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. Here, we identified an elevated type I interferon (IFN) signature in peripheral blood mononuclear cells and primary fibroblasts of DM2 patients as a trigger of chronic immune stimulation. Although RNA-repeat accumulation was prevalent in the cytosol of DM2-patient fibroblasts, type-I IFN release did not depend on innate RNA immune sensors but rather the DNA sensor cGAS and the prevalence of mitochondrial DNA (mtDNA) in the cytoplasm. Sublethal mtDNA release was promoted by a chronic activation of the ATF6 branch of the unfolded protein response (UPR) in reaction to RNA-repeat accumulation and non-AUG translated tetrapeptide expansion proteins. ATF6-dependent mtDNA release and resulting cGAS/STING activation could also be recapitulated in human THP-1 monocytes exposed to chronic endoplasmic reticulum (ER) stress. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic endoplasmic reticulum stress and associated mtDNA leakage. This mtDNA is, in turn, sensed by the cGAS/STING pathway and induces a type-I IFN response predisposing to autoimmunity. Elucidating this pathway reveals new potential therapeutic targets for autoimmune disorders associated with repeat expansion diseases.

DOI: https://doi.org/10.1038/s41467-024-45535-1

Cell Death Differ. 2024 Feb 23.

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.

Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.

DOI: https://doi.org/10.1038/s41418-024-01260-2

Adv Sci (Weinh). 2024 Feb 21. e2308009

RECQL4 Inhibits Radiation-Induced Tumor Immune Awakening via Suppressing the cGAS-STING Pathway in Hepatocellular Carcinoma.

Weifeng Hong, Yang Zhang, Siwei Wang, Zongjuan Li, Danxue Zheng, Shujung Hsu, Jian Zhou, Jia Fan, Zhesheng Chen, Xiaojun Xia, Zhaochong Zeng, Qiang Gao, Min Yu, Shisuo Du.

Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation-induced double-stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation-induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS-STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC-derived RECQL4 disrupts cGAS-STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.

Keywords: DNA repair; RecQ-Like Helicase 4; cGAS-STING pathway; hepatocellular carcinoma; tumor microenvironment

DOI: https://doi.org/10.1002/advs.202308009

Biomedicines. 2024 Feb 01. pii: 348. [Epub ahead of print]12(2):

Cutaneous Redox Senescence.

Mariáurea Matias Sarandy, Reggiani Vilela Gonçalves, Giuseppe Valacchi.

Our current understanding of skin cell senescence involves the role of environmental stressors (UV, O3, cigarette smoke, particulate matter, etc.), lifestyle (diet, exercise, etc.) as well as genetic factors (metabolic changes, hormonal, etc.). The common mechanism of action of these stressors is the disturbance of cellular redox balance characterized by increased free radicals and reactive oxygen species (ROS), and when these overload the intrinsic antioxidant defense system, it can lead to an oxidative stress cellular condition. The main redox mechanisms that activate cellular senescence in the skin involve (1) the oxidative damage of telomeres causing their shortening; (2) the oxidation of proteomes and DNA damage; (3) an a in lysosomal mass through the increased activity of resident enzymes such as senescence-associated β-galactosidase (SA-β-gal) as well as other proteins that are products of lysosomal activity; (4) and the increased expression of SASP, in particular pro-inflammatory cytokines transcriptionally regulated by NF-κB. However, the main targets of ROS on the skin are the proteome (oxi-proteome), followed by telomeres, nucleic acids (DNAs), lipids, proteins, and cytoplasmic organelles. As a result, cell cycle arrest pathways, lipid peroxidation, increased lysosomal content and dysfunctional mitochondria, and SASP synthesis occur. Furthermore, oxidative stress in skin cells increases the activity of p16INK4A and p53 as inhibitors of Rb and CDks, which are important for maintaining the cell cycle. p53 also promotes the inactivation of mTOR-mediated autophagic and apoptotic pathways, leading to senescence. However, these markers alone cannot establish the state of cellular senescence, and multiple analyses are encouraged for confirmation. An updated and more comprehensive approach to investigating skin senescence should include further assays of ox-inflammatory molecular pathways that can consolidate the understanding of cutaneous redox senescence.

Keywords: biochemistry; cutaneous senescence; inflammation; molecular signaling; reactive oxygen species

DOI: https://doi.org/10.3390/biomedicines12020348

Cell Death Differ. 2024 Feb 21.

DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response.

Huipeng Jiao, Sharmy J James, Chin Wen Png, Chaoyu Cui, Heng Li, Liang Li, Wan Ni Chia, Nyo Min, Weiyun Li, Carla Claser, Laurent Rénia, Hongyan Wang, Mark I-Cheng Chen, Justin Jang Hann Chu, Kevin Shyong Wei Tan, Yinyue Deng, Yongliang Zhang.

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.

DOI: https://doi.org/10.1038/s41418-024-01269-7