Trends in Cell Biology最新文献

Recent studies revealed how nucleolar stress enhances MDM4 exon skipping and activates p53 via the ribosomal protein L22 (RPL22; eL22). Tumor-associated L22 mutations lead to full-length MDM4 synthesis, overcoming tumor suppression by p53. This forum article explores how MDM4 splicing patterns integrate stress signaling to take p53-dependent cell fate decisions.

Tumors often face energy deprivation due to mutations, hypoxia, and nutritional deficiencies within the harsh tumor microenvironment (TME), and as an effect of anticancer treatments. This metabolic stress triggers adaptive reprogramming of mRNA translation, which in turn adjusts metabolic plasticity and associated signaling pathways to ensure tumor cell survival. Emerging evidence is beginning to reveal the complex interplay between metabolism and mRNA translation, shedding light on the mechanisms that synchronize ribosome assembly and reconfigure translation programs under metabolic stress. This review explores recent advances in our understanding of the coordination between metabolism and mRNA translation, offering insights that could inform therapeutic strategies targeting both cancer metabolism and translation, with the aim of disrupting cancer cell plasticity and survival.

Protein misfolding and aggregation in the endoplasmic reticulum (ER) have been causally linked to a variety of human diseases. Two key pathways for eliminating misfolded proteins and aggregates in the ER are ER-associated degradation (ERAD) and ER-phagy, respectively. While both pathways have been well characterized biochemically, our understanding of their physiological relevance and significance remains limited. In recent years, significant advances have been made, including the generation and characterization of various knockout and knockin mouse models, the identification of human disease-associated or -causing variants, and insights into the coordination between ERAD and autophagy in physiological contexts. In this review, we summarize these advancements, highlighting the key roles of a highly conserved suppressor of lin-12-like-hydroxymethyl glutaryl-coenzyme A reductase degradation 1 (SEL1L-HRD1) protein complex of ERAD and ER-phagy in health and disease.

The majority of the DNA sequence in our genome is noncoding and not intended for synthesizing proteins. Nonetheless, genome-wide mapping of ribosome footprints has revealed widespread translation in annotated noncoding sequences, including long noncoding RNAs (lncRNAs), untranslated regions (UTRs), and introns of mRNAs. How cells suppress the translation of potentially toxic proteins from various noncoding sequences remains poorly understood. This review summarizes mechanisms for the mitigation of noncoding translation, including the BCL2-associated athanogene 6 (BAG6)-mediated proteasomal degradation pathway, which has emerged as a unifying mechanism to suppress the translation of diverse noncoding sequences in metazoan cells.

Cells must sense and respond to numerous stimuli to maintain their function. Stress-activated protein kinases (SAPKs) are part of an integrated network that responds to these stimuli and have critical roles in determining cell behavior. Over the past 5 years, ribosomes and the ribotoxic stress response (RSR) have unexpectedly emerged as critical regulators of the SAPK network and drivers of global cell fate changes. In particular, RSR-SAPK signaling has potent effects on cellular proliferation, with important implications for senescence and cancer. In this review, we discuss cell cycle regulation by the SAPK p38, with a particular focus on how ribotoxic stress affects key cell cycle transitions.

Tight mitochondria-endoplasmic reticulum (ER) contacts (MERCS) play essential roles in cellular homeostasis. Brar et al. reveal a novel mechanism where mitochondrial mRNAs escape global translational repression at novel context-specific MERCS during ER stress, uncovering spatially regulated translation as a critical adaptive strategy to cope with cellular stress.

Aging trajectories vary among individuals, characterized by progressive functional decline, often leading to disease states. One of the central hallmarks of aging is the deterioration of proteostasis, where the function of the endoplasmic reticulum (ER) is dramatically affected. ER stress is monitored and adjusted by the unfolded protein response (UPR); a signaling pathway that mediates adaptive processes to restore proteostasis. Studies in multiple model organisms (yeast, worms, flies, and mice) in addition to human tissue indicates that adaptive UPR signaling contributes to healthy aging. Strategies to improve ER proteostasis using small molecules and gene therapy reduce the decline of organ function during normal aging in mammals. This article reviews recent advances in understanding the significance of the ER proteostasis network to normal aging and its relationship with other hallmarks of aging such as senescence.

Next to their essential role as protein production factories, ribosomes serve as molecular sensors of cell stress. Stalled and collided ribosomes trigger specific stress signaling, including the ribotoxic stress response (RSR). The RSR is initiated by the mitogen-activated protein (MAP)-3 kinase ZAKα in response to a plethora of translational aberrations, leading to activation of the stress-activated MAP kinases p38 and jun N-terminal kinase (JNK). Recent insights have highlighted an important role for the RSR pathway in triggering programmed cell death processes, including apoptosis and pyroptosis, in a broad range of physiologically relevant conditions. In this review, we summarize recent work on known links between programmed and accidental ribosome toxicity, RSR signaling, and cell death.

Ribosomal RNAs (rRNA) are the most abundant RNA molecules in almost all cell types. The general consensus in the field is that rRNA modifications are largely species-specific, with most previous works and databases solely stratifying modifications by the species of origin, without taking other levels of complexity into account. However, new evidence has emerged suggesting dynamic rRNA modifications may have additional layers of complexity and might play an important role in development and disease. In this review article, we summarize recent evidence supporting heterogeneity and dynamics in rRNA modifications in diverse biological contexts, challenging the simplistic view of 'one-species-one-rRNA-modification-pattern'. Moreover, we highlight how rRNA modification dynamics have been studied to date and how long-read sequencing methods can significantly improve our understanding of this largely unexplored yet highly abundant RNA family, across tissues, developmental stages, and diseases.