Adaptation of cells to new environments

Adaptation of cells to new environments

https://reasonandscience.catsboard.com/t2061p125-my-articles#6174

Several life-essential EPIGENETIC mechanisms respond to environmental stress. 

- heat shock factors (HSFs)
- The unfolded protein response (UPR)
- nonhomologous end-joining and homologous recombination
- The DNA Damage Response
- The Response to Oxidative Stress

Evolution takes supposedly thousands of years to gain an environmental advantage. So what environmental benefit would evolution supposedly provide, if adapting and responding to environmental stimuli is not only a life-essential process which had to be fully implemented when life began but, furthermore, a pre-programmed process based on information through signaling networks?


Cells have many mechanisms to modulate the signaling pathways at transcriptional, post-transcriptional and post-translational levels.

Organisms respond to short-term environmental changes by reversibly adjusting their physiology to maximize resource utilization while maintaining structural and genetic integrity by repairing and minimizing damage to cellular infrastructure, thereby balancing innovation with robustness. The cell’s initial response to a stressful stimulus is geared towards helping the cell to defend against and recover from the insult. 2 The fact that the cell’s survival critically depends on the ability to mount an appropriate response towards environmental or intracellular stress stimuli can explain why this reaction is highly conserved in evolution. The adaptive capacity of a cell ultimately determines its fate.

One of the reasons behind the evolutionary success of mammals (and other multicellular organisms) is their extraordinary capacity to adapt to changing environmental conditions. 3

Maybe the author should ask himself, how the Cell could have survived without the mechanism implemented from day one !!

If the stress stimulus does not go beyond a certain threshold, the cell can cope with it by mounting an appropriate protective cellular response, which ensures the cell’s survival. One of the main prosurvival activities of cells, the heat shock response, was originally described as the biochemical response of cells to mild heat stress (i.e., elevations in temperature of C above normal) During initiation of the heat shock response general protein transcription and translation is halted, presumably to alleviate the burden of misfolded proteins in the cell. However, transcription factors that enhance expression of a specific subset of protective genes are selectively activated under these conditions; these are the heat shock factors (HSFs) Vertebrate cells have three different HSFs: HSF1 is essential for the heat shock response and is also required for developmental processes, HSF2 and HSF4 are important for differentiation and development, while HSF3 is only found in avian cells and is probably redundant with HSF1 .

Secretory and membrane proteins undergo posttranslational processing, including glycosylation, disulfide bond formation, correct folding, and oligomerization, in the ER. In order to effectively produce and secrete mature proteins, cellular mechanisms for monitoring the ER environment are essential. Exposure of cells to conditions such as glucose starvation, inhibition of protein glycosylation, disturbance of Ca2+ homeostasis and oxygen deprivation causes accumulation of unfolded proteins in the ER (ER stress) and results in the activation of a well-orchestrated set of pathways during a phenomenon known as the unfolded protein response (UPR)

Upon cellular stress conditions that are caused by exposure to chemotherapeutic agents, irradiation, or environmental genotoxic agents such as polycyclic hydrocarbons or ultraviolet (UV) light, damage to DNA is a common initial event DNA double-strand breaks (DSBs) and single-strand breaks (SSBs) are considered as key lesions that initiate the activation of the DNA damage response. Damage to DNA engages DNA repair processes to ensure the cell’s survival in the case of sublethal damage. Depending on the type of lesion, DNA damage initiates one of several mammalian DNA repair pathways, which eventually restore the continuity of the DNA double strand. There are two main pathways for the repair of DSBs, that is, nonhomologous end-joining and homologous recombination

Cell survival requires appropriate proportions of molecular oxygen and various antioxidants. Reactive products of oxygen are amongst the most potent and omnipresent threats faced by cells. These include ROS such as

superoxide anion
hydrogen peroxide (H2O2)
singlet oxygen
hydroxyl radical (OH•)
peroxy radicals
the second messenger nitric oxide (NO•) which can react with O2 to form peroxynitrite (ONOO−)

Infectious agents can drive a plethora of stress responses by activating pattern recognition receptors. In the initiation of innate immune responses against pathogens, pattern-recognition receptors (PRRs) have an essential role in recognizing specific components of microorganisms and triggering responses that eliminate the invading microorganisms. However, inappropriate activation of PRRs can lead to prolonged inflammation and even to autoimmune and inflammatory diseases. Thus, PRR-triggered responses are regulated through the degradation or translocation of the innate receptors themselves and through the involvement of intracellular regulators or amplifiers. In addition, a complex interplay between PRRs and/or other immune pathways finely tunes the outcome of host immune defense responses. 4

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. Such mechanisms of cellular adaptation to stress contribute to the formidable resilience of the organism but can also contribute to its degeneration over time. 3

Normally in cells there exists equilibrium between pro-oxidant species and antioxidant defense mechanisms such as ROS-metabolizing enzymes including catalase, glutathione peroxidase, and superoxide dismutases (SODs) and other antioxidant proteins such as glutathione (GSH)

For the preservation of organismal homeostasis, as severely damaged, irreversibly infected, functionless and/or potentially oncogenic cells are destined for persistent inactivation or elimination, respectively.

It has become apparent that most (if not all) mechanisms of cellular response to stress are also associated with paracrine and endocrine signals that communicate a potential threat to the organism and hence contribute to the maintenance of systemic homeostasis. 


Signaling pathways and regulators of PRRs. 
Pattern-recognition receptors (PRRs) share intracellular pathways that lead to the production of pro-inflammatory cytokines and type I interferons (IFNs). 
a | All the Toll-like receptors (TLRs), except for TLR3, interact with MYD88 to induce the activation of nuclear factor-κB (NF‑κB) and mitogen-activated protein kinases (MAPKs), which induce the transcription factor activator protein 1 (AP-1), for the induction of pro-inflammatory cytokine expression. The TIR domain-containing adaptor protein inducing IFNβ (TRIF) pathway is shared by TLR4 and TLR3, and induces the activation of interferon regulatory factors IRF3–IRF7 for the production of type I IFNs.
b | Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) first interact with mitochondrial antiviral signaling protein (MAVS) and then activate signaling cascades through stimulator of interferon genes (STING) and TANK-binding kinase 1 (TBK1), leading to the expression of type I IFNs. MAVS also signals through receptor-interacting serine/threonine protein kinase 1 (RIPK1) for AP‑1 activation. 
c | Many cytosolic DNA and RNA sensors, including cyclic GMP–AMP synthase (cGAS), double-strand break repair protein MRE11, IFNγ-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA‑PK), the probable ATP-dependent RNA helicases DDX41 and DDX60, leucine-rich repeat flightless interacting protein 2 (LRRFIP2) and protein kinase RNA-activated (PKR), recognize intracellular DNA or RNA and converge on STING to drive type I IFNs and cytokine production. The ATP-dependent RNA helicases DHX9 and DHX36 recognize CpG-containing DNA and induce the MYD88‑dependent signalling pathway. 
d | NOD-like receptors (NLRs) are activated upon cellular infection or stress, and engage innate immune responses via RIPK2–NF‑κB signalling activation. Some NLRs, such as NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), ICE protease-activating factor (IPAF) and NLR apoptosis inhibitory protein 5 (NAIP5), form inflammasomes that contain the apoptosis-associated speck-like protein containing a CARD (ASC) and caspase 1, and trigger the maturation of interleukin-1β (IL-1β). 4


1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081528/
2. https://www.hindawi.com/journals/ijcb/2010/214074/
3. https://www.nature.com/articles/s41580-018-0068-0?subid1=20221026-1100-457b-8630-134ba6da965b
4. https://pubmed.ncbi.nlm.nih.gov/26711677/

Lorenzo Galluzzi (2018): 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.

Mammals (and other multicellular organisms) have an extraordinary capacity to adapt to changing environmental conditions. In over three decades of cell biology research, we obtained considerable insights into the molecular mechanisms whereby individual cells (attempt to) cope with perturbations of homeostasis. Such mechanisms of cellular adaptation to stress contribute to the formidable resilience of the organism but can also contribute to its degeneration over time, invariably culminating in ageing and/or disease. Prominent examples of perturbations that induce cell stress include DNA-damaging agents, which activate repair pathways specific for different types of genetic lesion; heat shock or chemical toxins that cause protein denaturation, both of which activate the unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria; hypoxia, respiratory poisons and xenobiotics that cause mitochondrial stress; nutrient deprivation, which activates autophagy in most cells of the organisms, hence enabling them to catabolize their own components for survival; and infectious agents, which can drive a plethora of stress responses by activating pattern recognition receptors . The triggers, receptors, signal transducers, effector mechanisms and adaptive responses that operate at the cellular level in each of these scenarios have been characterized in great molecular detail. As a common theme, it appears that perturbations of cellular homeostasis either lead to management of stress and damage repair — generally along with transient alterations in cellular metabolism — or culminate in cellular senescence or regulated cell death (RCD) when the restoration of normal cellular functions is impossible. The latter scenarios may be viewed as mechanisms for the preservation of organismal homeostasis, as severely damaged, irreversibly infected, functionless and/or potentially oncogenic cells are destined for persistent inactivation or elimination, respectively. It has become apparent that most (if not all) mechanisms of cellular response to stress are also associated with paracrine and endocrine signals that communicate a potential threat to the organism and hence contribute to the maintenance of systemic homeostasis1,12–14 (Fig. 1). This intercellular communication is achieved via multiple mechanisms, including (but not limited to) alterations in the shape of stressed cells and their connections with the microenvironment; the exposure of specific molecules on their surface; and the active or passive release of bioactive factors such as ions, small metabolites, intracellular proteins, cytokines or microvesicles. Here, we review how distinct stress responses are relayed from the intracellular to the extracellular milieu, how such communication favours the maintenance of organismal homeostasis and how deviations from its normal course may drive maladaptation and disease.

Lorenzo Galluzzi Linking cellular stress responses to systemic homeostasis 2018 Nov