Linking cellular stress responses to systemic homeostasis

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. *

Autophagy-Independent Functions of the Autophagy Machinery

“…Mice with conditional Ulk1/Ulk2 co-deletion in the brain surviving the first 24 h after birth resemble their Atg5-and Atg7-deficient counterparts as they display abnormal limb-clasping reflexes, but they do not develop cerebellar ataxia, suggesting that the neuronal phenotype caused by the lack of Ulk1 and Ulk2 may not result from an autophagic defect . Indeed, Ulk1 À/À Ulk2 À/À neurons do not exhibit accumulation of autophagic substrates such as sequestosome 1 (SQSTM1, best known as p62) but manifest signs of the unfolded protein response Wang et al, 2018), an intracellular pathway of adaptation to accumulation of unfolded polypeptides in the ER lumen (Galluzzi et al, 2018b). Consistently, both ULK1 and ULK2 can phosphorylate SEC16 homolog A, endoplasmic reticulum export factor (SEC16A) to drive the anterograde transport of ER-derived vesicles to the GA, and this pathway is insensitive to depletion of ATG13 (which is required for the pro-autophagic functions of ULKs), ATG14, and ATG7 .…”

“…In the latter case, RCD is a consequence of failing adaptation to stress. That said, stress-driven RCD can also be viewed as a mechanism for the maintenance of organismal homeostasis, as it underlies the removal of damaged, non-functional, and potentially oncogenic cells (Galluzzi et al, 2018b). The molecular mechanisms whereby mammalian cells undergo RCD in physiological and pathological scenarios exhibit considerable overlap.…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…The reasons behind the evolutionary success of mammals and other multicellular organisms is their extraordinary capacity to adapt to changing environmental conditions and survive by maintaining their homeostasis (1). Homeostasis refers to the relative stability in the activity of the physiological systems of the organism that are essential to support life (2).…”

Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

“…While the basal constitutive autophagy serves to clear undesired cellular substances, cells initiate adaptive autophagy in response to intracellular and extracellular cues such as nutrient limitation, DNA damage, and oxidative stress [1]. While the basal constitutive autophagy serves to clear undesired cellular substances, cells initiate adaptive autophagy in response to intracellular and extracellular cues such as nutrient limitation, DNA damage, and oxidative stress [1].…”