The phosphoinositide 3-kinase (PI3K) family is important to nearly all aspects of cell and tissue biology and central to human cancer, diabetes and aging. PI3Ks are spatially regulated and ...multifunctional, and together, act at nearly all membranes in the cell to regulate a wide range of signaling, membrane trafficking and metabolic processes. There is a broadening recognition of the importance of distinct roles for each of the three different PI3K classes (I, II and III), as well as for the different isoforms within each class. Ongoing issues include the need for a better understanding of the in vivo complexity of PI3K regulation and cellular functions. This Cell Science at a Glance article and the accompanying poster summarize the biochemical activities, cellular roles and functional requirements for the three classes of PI3Ks. In doing so, we aim to provide an overview of the parallels, the key differences and crucial interplays between the regulation and roles of the three PI3K classes.
Membrane trafficking relies on dynamic changes in membrane identities that are determined by the regulation of distinct RAB GTPases and phosphoinositides. RABs and phosphoinositides both act to ...spatiotemporally recruit effectors of membrane remodelling, including sequential RAB and phosphoinositide activities. New ideas on coordinated regulation of specific RABs and phosphoinositides, achieved by direct physical and functional interactions between their regulatory enzymes, are emerging as a central mechanism to ensure precision and fidelity of membrane trafficking.
Metallic nanoparticles (mNPs) are widely used as food additives and can interact with gliadin triggering an immune response, but evaluation of the effects on crypts, hypertrophic in celiac subjects, ...is still lacking. This study evaluated the effects of gold and silver mNPs in combination with gliadin on crypt-like cells (HIEC-6). Transmission electron microscopy (TEM) was used to evaluate gliadin-mNP aggregates in cells. Western blot and immunofluorescence analysis assessed autophagy-related molecule levels (p62, LC3, beclin-1, EGFR). Lysosome functionality was tested with acridine orange (AO) and Magic Red assays. TEM identified an increase in autophagic vacuoles after exposure to gliadin + mNPs, as also detected by significant increments in LC3-II and p62 expression. Immunofluorescence confirmed the presence of mature autophagosomes, showing LC3 and p62 colocalization, indicating an altered autophagic flux, further assessed with EGFR degradation, AO and Magic Red assays. The results showed a significant reduction in lysosomal enzyme activity and a modest reduction in acidity. Thus, gliadin + mNPs can block the autophagic flux inducing a lysosomal defect. The alteration of this pathway, essential for cell function, can lead to cell damage and death. The potential effects of this copresence in food should be further characterized to avoid a negative impact on celiac disease subjects.
Rabs in Signaling and Embryonic Development Nassari, Sonya; Del Olmo, Tomas; Jean, Steve
International journal of molecular sciences,
02/2020, Letnik:
21, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are ...crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.
Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules ...maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms.
Macroautophagy/autophagy is coupled to a myriad of intracellular processes, among which vesicular trafficking is an important contributor of membranes and proteins required at various stages, from ...autophagosome formation to degradation. Hence, understanding how membrane trafficking is coupled to autophagy induction and how cells rewire trafficking upon high autophagic needs is instrumental to our understanding of autophagy. In our recent manuscript, we tested a known class of endosomal sorting regulators, the sorting nexin family, for their involvement in autophagy in Drosophila. We identified snz (snazarus) as an important regulator of autophagy in Drosophila as well as in mammalian cells, by demonstrating a role for the snz human ortholog SNX25 in HeLa cells. Using knockout rescue experiments, we observed that SNX25 loss affects many cellular processes, namely VAMP8 endocytosis and lipid handling. Mutational studies identified separate protein domains involved in these processes. Given the role of this sorting nexin family in lipid droplet regulation, our work expands their requirement to autophagy.
Endosomes are a heterogeneous population of intracellular organelles responsible for sorting, recycling, or transporting internalized materials for degradation. Endosomal sorting and maturation are ...controlled by a complex interplay of regulators, with RAB GTPases and phosphoinositides playing key roles. In this decade, another layer of regulation surfaced with the role played by membrane contact sites between the endoplasmic reticulum (ER) and endosomes. Specific regulators of ER-endosome contact sites or proteins localized at these sites are emerging as modulators of this complex endosomal ballet. In particular, lipid transfer or recruitment of various complexes and enzymes at ER-endosome contact sites play an active role in endosome sorting, scission, and maturation. In this short review, we focus on studies describing ER-endosome contact sites in these three endosomal processes.
Due to the fast growth of data that are measured on a continuous scale, functional data analysis has undergone many developments in recent years. Regression models with a functional response ...involving functional covariates, also called “function-on-function”, are thus becoming very common. Studying this type of model in the presence of heterogeneous data can be particularly useful in various practical situations. We mainly develop in this work a function-on-function Mixture of Experts (FFMoE) regression model. Like most of the inference approach for models on functional data, we use basis expansion (B-splines) both for covariates and parameters. A regularized inference approach is also proposed, it accurately smoothes functional parameters in order to provide interpretable estimators. Numerical studies on simulated data illustrate the good performance of FFMoE as compared with competitors. Usefullness of the proposed model is illustrated on two data sets: the reference Canadian weather data set, in which the precipitations are modeled according to the temperature, and a Cycling data set, in which the developed power is explained by the speed, the cyclist heart rate and the slope of the road.
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