Trends in Cell Biology最新文献

Alternative mRNA splicing enables the diversification of the proteome from a static genome and confers plasticity and adaptiveness on cells. Although this is often explored in development, where hard-wired programs drive the differentiation and specialization, alternative mRNA splicing also offers a way for cells to react to sudden changes in outside stimuli such as small-molecule metabolites. Fluctuations in metabolite levels and availability in particular convey crucial information to which cells react and adapt. We summarize and highlight findings surrounding the metabolic regulation of mRNA splicing. We discuss the principles underlying the biochemistry and biophysical properties of mRNA splicing, and propose how these could intersect with metabolite levels. Further, we present examples in which metabolites directly influence RNA-binding proteins and splicing factors. We also discuss the interplay between alternative mRNA splicing and metabolite-responsive signaling pathways. We hope to inspire future research to obtain a holistic picture of alternative mRNA splicing in response to metabolic cues.

Animal oocytes face extreme challenges. They remain dormant in the body for long periods of time. To support offspring development and health, they need to store genetic material and maternal factors stably and at the same time manage cellular damage in a reliable manner. Recent studies have provided new insights on how oocytes cope with such challenges. This review discusses the many unusual or idiosyncratic nature of oocytes and how understanding oocyte biology can help us address issues of reproduction and intergenerational inheritance.

Stem cells persist throughout the lifespan to repair and regenerate tissues due to their unique ability to self-renew and differentiate. Here we reflect on the recent discoveries in stem cells that highlight a mitochondrial metabolic checkpoint at the restriction point of the stem cell cycle. Mitochondrial activation supports stem cell proliferation and differentiation by providing energy supply and metabolites as signaling molecules. Concomitant mitochondrial stress can lead to loss of stem cell self-renewal and requires the surveillance of various mitochondrial quality control mechanisms. During aging, a mitochondrial protective program mediated by several sirtuins becomes dysregulated and can be targeted to reverse stem cell aging and tissue degeneration, giving hope for targeting the mitochondrial metabolic checkpoint for treating tissue degenerative diseases.

Proteins are molecular machines that provide structure and perform vital transport, signalling and enzymatic roles. Proteins expressed by cells require tight regulation of their concentration, folding, localisation, and modifications; however, this state of protein homeostasis is continuously perturbed by tissue-level stresses. While cells in healthy tissues are able to buffer against these perturbations, for example, by expression of chaperone proteins, protein homeostasis is lost in ageing, and can lead to protein aggregation characteristic of protein folding diseases. Here, we review reports of a progressive disconnect between transcriptomic and proteomic regulation during cellular ageing. We discuss how age-associated changes to cellular responses to specific stressors in the tissue microenvironment are exacerbated by loss of ribosomal proteins, ribosomal pausing, and mistranslation.

The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders.

The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.

Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPR^mt) in Caenorhabditis elegans.

In the commonly accepted paradigm for control of the mammalian cell cycle, sequential cyclin-dependent kinase (CDK) and cyclin activities drive the orderly transition from G1 to S phase. However, recent studies using different technological approaches and examining a broad range of cancer cell types are challenging this established paradigm. An alternative model is evolving in which cell cycles utilize different drivers and take different trajectories through the G1/S transition. We are discovering that cancer cells in particular can adapt their drivers and trajectories, which has important implications for antiproliferative therapies. These studies have helped to refine an understanding of how CDK inhibition impinges on proliferation and have significance for understanding fundamental features of cell biology and cancer.