bims-ershed 2023-01-22 papers

Front Immunol. 2022 ;13 1063221

The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection.

Erika S Guimarães, Marco Túlio R Gomes, Rodrigo C O Sanches, Kely Catarine Matteucci, Fábio V Marinho, Sergio C Oliveira.

Endoplasmic reticulum (ER) stress plays a major role in several inflammatory disorders. ER stress induces the unfolded protein response (UPR), a conserved response broadly associated with innate immunity and cell metabolic function in various scenarios. Brucella abortus, an intracellular pathogen, triggers the UPR via Stimulator of interferon genes (STING), an important regulator of macrophage metabolism during B. abortus infection. However, whether ER stress pathways underlie macrophage metabolic function during B. abortus infection remains to be elucidated. Here, we showed that the UPR sensor inositol-requiring enzyme 1α (IRE1α) is as an important component regulating macrophage immunometabolic function. In B. abortus infection, IRE1α supports the macrophage inflammatory profile, favoring M1-like macrophages. IRE1α drives the macrophage metabolic reprogramming in infected macrophages, contributing to the reduced oxidative phosphorylation and increased glycolysis. This metabolic reprogramming is probably associated with the IRE1α-dependent expression and stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), an important molecule involved in cell metabolism that sustains the inflammatory profile in B. abortus-infected macrophages. Accordingly, we demonstrated that IRE1α favors the generation of mitochondrial reactive oxygen species (mROS) which has been described as an HIF-1α stabilizing factor. Furthermore, in infected macrophages, IRE1α drives the production of nitric oxide and the release of IL-1β. Collectively, these data unravel a key mechanism linking the UPR and the immunometabolic regulation of macrophages in Brucella infection and highlight IRE1α as a central pathway regulating macrophage metabolic function during infectious diseases.

Keywords: HIF-1α; IRE1α; UPR; brucella abortus; endoplasmic reticulum stress; immunometabolism

DOI: https://doi.org/10.3389/fimmu.2022.1063221

Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2216055120

Mammalian life depends on two distinct pathways of DNA damage tolerance.

Olimpia Alessandra Buoninfante, Bas Pilzecker, Aldo Spanjaard, Daniël de Groot, Stefan Prekovic, Ji-Ying Song, Cor Lieftink, Matilda Ayidah, Colin E J Pritchard, Judith Vivié, Kathleen E Mcgrath, Ivo J Huijbers, Sjaak Philipsen, Marieke von Lindern, Wilbert Zwart, Roderick L Beijersbergen, James Palis, Paul C M van den Berk, Heinz Jacobs.

DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.

Keywords: DNA damage response (DDR); DNA damage tolerance (DDT); embryonic lethality; erythropoiesis; hematopoietic stem cells

DOI: https://doi.org/10.1073/pnas.2216055120

Mutat Res Genet Toxicol Environ Mutagen. 2023 Jan;pii: S1383-5718(22)00126-7. [Epub ahead of print]885 503564

An investigation of DNA damage and DNA repair in chemical carcinogenesis triggered by small-molecule xenobiotics and in cancer: Thirty years with the comet assay.

Pavel Vodicka, Sona Vodenkova, Josef Horak, Alena Opattova, Kristyna Tomasova, Veronika Vymetalkova, Rudolf Stetina, Kari Hemminki, Ludmila Vodickova.

In the present review we addressed the determination of DNA damage induced by small-molecule carcinogens, considered their persistence in DNA and mutagenicity in in vitro and in vivo systems over a period of 30 years. The review spans from the investigation of the role of DNA damage in the cascade of chemical carcinogenesis. In the nineties, this concept evolved into the biomonitoring studies comprising multiple biomarkers that not only reflected DNA/chromosomal damage, but also the potential of the organism for biotransformation/elimination of various xenobiotics. Since first years of the new millennium, dynamic system of DNA repair and host susceptibility factors started to appear in studies and a considerable knowledge has been accumulated on carcinogens and their role in carcinogenesis. It was understood that the final biological links bridging the arising DNA damage and cancer onset remain to be elucidated. In further years the community of scientists learnt that cancer is a multifactorial disease evolving over several decades of individual´s life. Moreover, DNA damage and DNA repair are inseparable players also in treatment of malignant diseases, but affect substantially other processes, such as degeneration. Functional monitoring of DNA repair pathways and DNA damage response may cast some light on above aspects. Very little is currently known about the relationship between telomere homeostasis and DNA damage formation and repair. DNA damage/repair in genomic and mitochondrial DNA and crosstalk between these two entities emerge as a new interesting topic.

Keywords: Butadiene; DNA damage; DNA repair; Formaldehyde; Occupational medicine; Styrene

DOI: https://doi.org/10.1016/j.mrgentox.2022.503564