Role of Sphingosine Kinase 1 in Glucolipotoxicity-Induced Early Activation of Autophagy in INS-1 Pancreatic β Cells.

Insulin-producing pancreatic β cells play a crucial role in the regulation of glucose homeostasis, and their failure is a key event for diabetes development. Prolonged exposure to palmitate in the presence of elevated glucose levels, termed gluco-lipotoxicity, is known to induce β cell apoptosis. Autophagy has been proposed to be regulated by gluco-lipotoxicity in order to favor β cell survival.

Yapping at the autophagy door? The answer is flowing in the kidney proximal tubule.

Shear stress induced by urinary flow stimulates macroautophagy (hereafter referred to as autophagy) in kidney proximal tubule epithelial cells. Autophagy and selective degradation of lipid droplets by lipophagy contribute to tubule homeostasis by the production of ATP and control of epithelial cell size. Autophagy/lipophagy is controlled by a signaling cascade emanating from the primary cilium, localized at the apical side of epithelial cells.

Slc20a1 and Slc20a2 regulate neuronal plasticity and cognition independently of their phosphate transport ability.

In recent years, primary familial brain calcification (PFBC), a rare neurological disease characterized by a wide spectrum of cognitive disorders, has been associated to mutations in the sodium (Na)-Phosphate (Pi) co-transporter SLC20A2. However, the functional roles of the Na-Pi co-transporters in the brain remain still largely elusive. Here we show that Slc20a1 (PiT-1) and Slc20a2 (PiT-2) are the most abundant Na-Pi co-transporters expressed in the brain and are involved in the control of hippocampal-dependent learning and memory.

PI3KCIIα-Dependent Autophagy Program Protects From Endothelial Dysfunction and Atherosclerosis in Response to Low Shear Stress in Mice.

Background: The ability to respond to mechanical forces is a basic requirement for maintaining endothelial cell (ECs) homeostasis, which is continuously subjected to low shear stress (LSS) and high shear stress (HSS). In arteries, LSS and HSS have a differential impact on EC autophagy processes. However, it is still unclear whether LSS and HSS differently tune unique autophagic machinery or trigger specific autophagic responses in ECs.

The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells.

Shear stress generated by urinary fluid flow is an important regulator of renal function. Its dysregulation is observed in various chronic and acute kidney diseases. Previously, we demonstrated that primary cilium-dependent autophagy allows kidney epithelial cells to adapt their metabolism in response to fluid flow.

A historical perspective of macroautophagy regulation by biochemical and biomechanical stimuli.

Macroautophagy is a lysosomal degradative pathway for intracellular macromolecules, protein aggregates, and organelles. The formation of the autophagosome, a double membrane-bound structure that sequesters cargoes before their delivery to the lysosome, is regulated by several stimuli in multicellular organisms. Pioneering studies in rat liver showed the importance of amino acids, insulin, and glucagon in controlling macroautophagy.

Autophagy and the primary cilium in cell metabolism: What's upstream?

The maintenance of cellular homeostasis in response to extracellular stimuli, i.e., nutrient and hormone signaling, hypoxia, or mechanical forces by autophagy, is vital for the health of various tissues.

Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin.

Naked mole-rats (NMR) are subterranean rodents characterized by an unusual longevity coupled with an unexplained resistance to aging. In the present study, we performed extensive analysis and single-cell RNA-sequencing comparing young and older animals. At variance with other species, NMR exhibited a striking stability of skin compartments and cell types, which remained stable over time without aging-associated changes.

The sexual dimorphism of kidney growth in mice and humans.

Kidney mass and function are sexually determined, but the cellular events and the molecular mechanisms involved in this dimorphism are poorly characterized. By combining female and male mice with castration/replacement experiments, we showed that male mice exhibited kidney overgrowth from five weeks of age. This effect was organ specific, since liver and heart weight were comparable between males and females, regardless of age.

Primary cilium-dependent autophagy in the response to shear stress.

Mechanical forces, such as compression, shear stress and stretching, play major roles during development, tissue homeostasis and immune processes. These forces are translated into a wide panel of biological responses, ranging from changes in cell morphology, membrane transport, metabolism, energy production and gene expression. Recent studies demonstrate the role of autophagy in the integration of these physical constraints.

Links between autophagy and tissue mechanics.

Physical constraints, such as compression, shear stress, stretching and tension, play major roles during development, tissue homeostasis, immune responses and pathologies. Cells and organelles also face mechanical forces during migration and extravasation, and investigations into how mechanical forces are translated into a wide panel of biological responses, including changes in cell morphology, membrane transport, metabolism, energy production and gene expression, is a flourishing field. Recent studies demonstrate the role of macroautophagy in the integration of physical constraints.

Autophagy in major human diseases.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies.

Machinery, regulation and pathophysiological implications of autophagosome maturation.

Autophagy is a versatile degradation system for maintaining cellular homeostasis whereby cytosolic materials are sequestered in a double-membrane autophagosome and subsequently delivered to lysosomes, where they are broken down. In multicellular organisms, newly formed autophagosomes undergo a process called 'maturation', in which they fuse with vesicles originating from endolysosomal compartments, including early/late endosomes and lysosomes, to form amphisomes, which eventually become degradative autolysosomes. This fusion process requires the concerted actions of multiple regulators of membrane dynamics, including SNAREs, tethering proteins and RAB GTPases, and also transport of autophagosomes and late endosomes/lysosomes towards each other.

Monitoring lipophagy in kidney epithelial cells in response to shear stress.

Mechanical stress has been shown to induce the degradation of lipid droplets in kidney epithelial cells. Here, we illustrate the technical equipment and devices that are currently used in our laboratory to apply shear stress on cells. We provide a detailed protocol to monitor lipophagy in response to shear stress.

When the autophagy protein ATG16L1 met the ciliary protein IFT20.

The primary cilium (PC), a plasma membrane microtubule-based structure, is a sensor of extracellular chemical and mechanical stress stimuli. Upon ciliogenesis, the autophagy protein ATG16L1 and the ciliary protein IFT20 are co-transported to the PC. We demonstrated in a recent study that IFT20 and ATG16L1 interact in a multiprotein complex.

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation.

The cyclin-dependent kinase inhibitor p27 (p27) has been involved in promoting autophagy and survival in conditions of metabolic stress. While the signaling cascade upstream of p27 leading to its cytoplasmic localization and autophagy induction has been extensively studied, how p27 stimulates the autophagic process remains unclear. Here, we investigated the mechanism by which p27 promotes autophagy upon glucose deprivation.

The autophagy protein ATG16L1 cooperates with IFT20 and INPP5E to regulate the turnover of phosphoinositides at the primary cilium.

The primary cilium (PC) regulates signalization linked to external stress sensing. Previous works established a functional interplay between the PC and the autophagic machinery. When ciliogenesis is promoted by serum deprivation, the autophagy protein ATG16L1 and the ciliary protein IFT20 are co-transported to the PC.

ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration.

Despite the great advances in autophagy research in the last years, the specific functions of the four mammalian Atg4 proteases (ATG4A-D) remain unclear. In yeast, Atg4 mediates both Atg8 proteolytic activation, and its delipidation. However, it is not clear how these two roles are distributed along the members of the ATG4 family of proteases.

Correction: Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy.

[This corrects the article DOI: 10.1371/journal.ppat.

Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy.

Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells.