Linking Cellular Stress Responses to Systemic Homeostasis Lorenzo Galluzzi, Takahiro Yamazaki, Guido Kroemer

Linking cellular stress responses to systemic homeostasis Lorenzo Galluzzi, Takahiro Yamazaki, Guido Kroemer To cite this version: Lorenzo Galluzzi, Takahiro Yamazaki, Guido Kroemer. Linking cellular stress responses to systemic homeostasis. Nature Reviews Molecular Cell Biology, Nature Publishing Group, 2018, 19 (11), pp.731- 745. 10.1038/s41580-018-0068-0. hal-02022975 HAL Id: hal-02022975 https://hal.sorbonne-universite.fr/hal-02022975 Submitted on 18 Feb 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Linking cellular stress responses to systemic homeostasis Lorenzo Galluzzi1,2,3,10*, Takahiro Yamazaki1 and Guido Kroemer3,4,5,6,7,8,9,10* Abstract | Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses — which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy — as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells — such as cell senescence and regulated cell death — are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease. Pattern recognition One of the reasons behind the evolutionary success of molecular detail. As a common theme, it appears that receptors mammals (and other multicellular organisms) is their perturbations of cellular homeostasis either lead to Evolutionarily conserved extraordinary capacity to adapt to changing environ- manage ment of stress and damage repair — generally receptors that elicit mental conditions. In over three decades of cell biol- along with transient alterations in cellular metabolism — inflammation and innate regulated cell death immunity upon recognition of ogy research, we obtained considerable insights into or culminate in cellular senescence or conserved microbial products the molecular mechanisms whereby individual cells (RCD) when the restoration of normal cellular functions or endogenous danger signals. (attempt to) cope with perturbations of homeostasis. is impossible9,10. The latter scenarios may be viewed as Such mechanisms of cellular adaptation to stress con- mechanisms for the preservation of organismal homeo- Regulated cell death tribute to the formidable resilience of the organism stasis, as severely damaged, irreversibly infected, func- (RCD). Variant of cell death that relies on a dedicated, but can also contribute to its degeneration over time, tionless and/or potentially oncogenic cells are destined 1 11 genetically encoded machinery invariably culminating in ageing and/or disease . for persistent inactivation or elimination, respectively . and hence can be delayed Prominent examples of perturbations that induce It has become apparent that most (if not all) mech- or accelerated with cell stress include DNA- damaging agents (for example, anisms of cellular response to stress are also associated pharmacological or genetic interventions. ionizing radiation and some xenobiotics), which activate with paracrine and endocrine signals that communicate repair pathways specific for different types of genetic a potential threat to the organism and hence contribute lesion2; heat shock or chemical toxins that cause pro- to the maintenance of systemic homeostasis1,12–14 (Fig. 1). tein denaturation, both of which activate the unfolded This intercellular communication is achieved via multiple protein response (UPR) in the endoplasmic reticulum mechanisms, including (but not limited to) alterations in (ER) and mitochondria3,4; hypoxia, respiratory poisons the shape of stressed cells and their connections with the and xenobiotics that cause mitochondrial stress5; nutri- microenvironment; the exposure of specific molecules ent deprivation, which activates autophagy in most cells on their surface; and the active or passive release of bio- of the organisms, hence enabling them to catabolize active factors such as ions, small metabolites, intracellular their own components for survival6,7; and infectious proteins, cytokines or microvesicles. agents, which can drive a plethora of stress responses Here, we review how distinct stress responses are pattern recognition receptors8 *e- mail: [email protected]; by activating . The triggers, relayed from the intracellular to the extracellular milieu, [email protected] receptors, signal transducers, effector mechanisms and how such communication favours the maintenance of https://doi.org/10.1038/ adaptive responses that operate at the cellular level in organismal homeostasis and how deviations from its s41580-018-0068-0 each of these scenarios have been characterized in great normal course may drive maladaptation and disease. Cell cycle checkpoints Adaptation to cellular stress persist (although in a senescent, non- proliferative Control mechanisms that Multiple potentially detrimental perturbations of the state) and potentially contribute to tissue deterioration ensure the progression of intracellular or extracellular microenvironment can be and ageing (see below). Furthermore, accumulating eukaryotic cells along the cell successfully managed by mammalian cells upon the acti- evidence suggests that the DDR- mediated activation cycle only in the presence of favourable conditions. vation of stress responses that preserve cellular functions of NK cells contributes to the recognition and removal of and repair macromolecular damage. pre- malignant and malignant cells and supports Immunogenicity oncosuppression21,22. Of note, NK cell- activating lig- The ability to trigger an The DNA damage response. DNA damage leads to the ands can be shed by metalloproteinases secreted in immune response, resulting activation of cell cycle checkpoints coupled to the recruit- the tumour microenvironment, resulting in the gen- from antigenicity (the property of being recognized by immune ment of the DNA repair machinery to genetic lesions. eration of decoy molecules that inhibit (rather than 21 cells) and adjuvanticity (the If the DNA damage response (DDR) is unsuccessful, the activate) NK cells . property of delivering activating same machinery ultimately initiates cellular senescence DNA damage also initiates the secretion of soluble signals to immune cells). or RCD2 (BOx 1), both of which also impinge on the con- factors that regulate local inflammatory responses, both Natural killer (NK) cells trol of microenvironmental and systemic homeo stasis in the context of cellular senescence and independently A group of cells from the innate (see separate sections below). Importantly, the DDR of it. One of the mechanisms underlying this process lymphoid immune system itself is also intimately connected with the elimination involves the DNA damage- associated release of nuclear that can mediate cytotoxic of damaged cells by immune effectors and the estab- DNA fragments into the cytoplasm23–26. Cytosolic DNA functions independent of lishment of inflammatory responses that contribute to is recognized by cyclic GMP- AMP synthase (cGAS), antigen recognition. the maintenance of local and systemic homeostasis15. which drives the activation of stimulator of interferon Major histocompatibility In some cases, however, such responses can favour genes (STING; encoded by TMEM173) and the conse- complex maladaptation and contribute to the establishment quent production of type I interferon (IFN)27,28. Because (MHC). Set of cell surface of pathological conditions, especially in the presence of type I IFN is a strongly pro- inflammatory cytokine, proteins essential for the immune system to recognize molecular defects in the mechanisms that physiologically its production needs to be tightly regulated to avoid 16 foreign molecules in extinguish inflammation . tissue damage related to uncontrolled inflammation. vertebrates. DNA- damaging agents including ionizing radiation Type I IFN secretion driven by cytosolic DNA recog- are known for their ability to change the immunogenicity nition is negatively controlled by cytosolic nucleases, Abscopal responses of affected cells, hence facilitating their recognition by including three- prime repair exonuclease 1 (TREX1) Measurable reductions in the natural killer (NK) cells (REFS29,30) (Fig. 2a) size of a non- irradiated tumour cytotoxic T lymphocytes (CTLs) or . and RNase H2 . Accordingly, loss- or metastasis thereof following Activation of the DDR has

Load more