FEBS Letters最新文献

The maintenance of protein homeostasis is a fundamental premise for the survival of all life. The synthesis, folding, localization, and degradation of thousands of proteins must be organized according to various conditions. To ensure such a stable and functional proteome, the proteostasis network evolved. Dedicated to this, the fourth School on Proteostasis, a co-funded EMBO|FEBS Lecture Course in memory of Susan Lindquist, took place in Espoo, Finland on 16–19 September 2025, with 59 early career researchers (PhD students or postdoctoral fellows), 18 leading scientists, and two editors attending and discussing the current state of the field. From basic principles to the latest therapeutic developments, this meeting provided a comprehensive overview of proteostasis. This report summarizes the lecture course and highlights selected presentations.

Parenthood has been linked to lower retention of women in academia, yet the specific challenges faced by mothers remain underexplored. We interviewed nine mothers across different career stages in the life sciences to qualitatively examine how motherhood intersects with academic milestones. Participants described challenges unique to academia, including dependence on supervisors, publication pressure, financial strain, and limited awareness of available institutional resources. They also shared strategies that supported their success, such as transparent communication with supervisors, designating student–parent coordinators, and creating peer communities for mothers in academia. By highlighting shared barriers and effective solutions, this work underscores the need for structural and cultural reforms to better support mothers in academia and retain talented scientists in STEM fields.

Almost all organisms on earth undergo rhythmic physiological and behavioral changes over the course of day. These rhythms are fundamental in most organisms and are referred to as circadian rhythms. The molecular mechanisms regulating these changes have evolved significantly in different kingdoms of life and they engage in crosstalk with most cellular functions. These molecular mechanisms have been studied for a long time using different model organisms and carefully designed experiments. In the past two decades or so, with advances in high throughput technologies and access to ever increasing computational power, the molecular mechanisms regulating circadian rhythms are being explored at multiple spatial and temporal scales. In this review, we introduce diverse regulatory mechanisms of circadian rhythms. We then focus on the proteins involved in circadian regulation, their structures, complexes and dynamics. This is followed by a review of computational methods such as structural modeling, integrative modeling and molecular simulations as applied to understanding the clock proteins in different organisms and insights obtained from the same. Finally, we highlight the limitations and future prospects of these methods in understanding the circadian regulation.

ETS family transcription factors can mediate mutant p53 functions, but there has been no comprehensive analysis of p53 interaction across the ETS family. By comparing direct mutant p53 binding between 26 ETS proteins, we found that all bound mutant p53, but relative binding differed significantly. The ETS DNA binding domain provided a common interaction interface, but strong binding required an alternate interaction domain highlighted by a PXXPP motif found in five ETS proteins. Genome-wide mapping found that the ETS protein ERG mediated some mutant p53 DNA binding in prostate cancer cells. Lastly, ETS proteins that interact strongly with mutant p53 tended to be upregulated in p53 mutant ovarian cancer. These results identify multiple ETS family members that could mediate mutant p53 function in cancer. Impact statement The mechanisms behind gain-of-function mutant p53 remain unclear. Here we identify distinct domains and a novel motif that can mediate binding of mutant p53 to multiple different ETS family transcription factors.

During gene expression, ribosome stalling frequently occurs and can lead to detrimental effects on cellular homeostasis. Several quality control mechanisms, including ribosome-associated quality control (RQC) and nonfunctional ribosomal RNA decay (NRD), have been identified to resolve these aberrant translation events. While the molecular mechanisms of each pathway have been extensively characterized, the mechanisms underlying the mutual regulation of the expression of pathway factors remain to be elucidated. Here, we employed a series of knockout mouse and human cell lines to investigate the crosstalk between translational quality control factors. Our findings revealed that the E3 ubiquitin ligase LTN1 suppresses expression of the E3 ubiquitin ligase RNF10 in a manner dependent on the RING domain of LTN1. This discovery offers new insights into the coordination of translational surveillance pathways.

EXPRESSION OF CONCERN: A. Li, X. Lin, X. Tan, B. Yin, W. Han, J. Zhao, J. Yuan, B. Qiang, and X. Peng, “ Circadian Gene Clock Contributes to Cell Proliferation and Migration of Glioma and Is Directly Regulated by Tumor-Suppressive miR-124,” FEBS Letters 587, no. 15 (2013): 2455-2460, https://doi.org/10.1016/j.febslet.2013.06.018.

This Expression of Concern is for the above article, published online on 19 June 2013, in Wiley Online Library (http://onlinelibrary.wiley.com/), and has been issued by agreement between the journal Editor-in-Chief, Michael Brunner; FEBS Press; and John Wiley and Sons Ltd. A third party reported that the siNC and siCLOCK images for U87MG cells in Figure 2D shared an overlapping section. An investigation by the journal confirmed these concerns.

The authors responded to an inquiry by the journal and supplied what were labeled as original data and a request for correction. The authors stated that the error in Figure 2D was caused by a mistake in the image compilation process. The journal reviewed the data provided, but they were unable to validate the experimental procedures used to generate the data. The journal reviewed the data provided, but were unable to confirm that it was acquired during the original study period. As such, the journal does not view a correction as appropriate. The Expression of Concern has been agreed to in order to inform and alert readers of the image overlap in Figure 2D. The authors disagree with the Expression of Concern.

Cutaneous leishmaniasis (CL) presents diverse clinical challenges due to species-specific drug efficacy and resistance. We propose a novel therapeutic strategy using synthetic biology to reprogram macrophage responses. By engineering an inducible TET-ON gene circuit to express immunomodulatory PeptideA (PepA), we enhance IL-12 production and parasite clearance. Peptides were identified via AI and validated through molecular dynamics simulations. This approach shifts macrophages toward a pro-inflammatory M1 phenotype, improving infection outcomes. Delivery via Tac-6 nanogel and adoptive transfer enables in vivo expression. Our method offers targeted, controllable treatment for CL, potentially overcoming current limitations. This platform also provides a versatile pipeline for studying macrophage-associated infections and inflammatory diseases, paving the way for precision immunotherapy. Impact statement We present a synthetic biology-based approach to treat cutaneous leishmaniasis by reprogramming macrophages with an inducible gene circuit expressing AI-designed peptides that boost IL-12 production and parasite clearance. Delivered via Tac-6 nanogel, this strategy offers targeted, resistance-mitigating therapy and a versatile platform for macrophage-driven diseases.

The brain vasculature is a critical barrier to maintain central nervous system (CNS) homeostasis. Parasitic infections can profoundly disrupt the brain vasculature, with consequences ranging from subtle neurological alterations to severe, life-threatening pathologies. In this review, we explore the diverse mechanisms by which endoparasites interact with, modulate and breach CNS blood and lymphatic vessels. We highlight how these pathogens manipulate endothelial function, alter barrier permeability and exploit vascular surface molecules to access or influence the brain. These interactions often trigger local inflammation, endothelial activation and blood-brain barrier breakdown, with significant implications for parasite survival and host pathology. Here, we review the molecular and cellular mechanisms underlying these processes, providing an integrative view of parasite-vascular crosstalk in the brain and identifying emerging research areas. Understanding these interactions offers new insights into brain vascular disease pathogenesis and may inform future strategies for intervention.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a pivotal role in mounting an innate immune response against invading pathogens. Activation of this pathway by exogenous or endogenous stimuli triggers the downstream production of interferons and both pro-/anti-inflammatory cytokines. Over the past decade, hundreds of patents have been filed for the development and use of natural and synthetic STING agonists. For antivirals, synthetic STING agonists have been shown to be effective in both prophylactic and anaphylactic manners against viral infection and serve as vaccine adjuvants. This review summarizes the current application of STING agonists as antivirals to date against a variety of RNA and DNA viruses.

Phosphoinositides are transient signaling lipids, derived from the reversible phosphorylation of phosphatidylinositol on intracellular membranes, which serve as master regulators of many essential cellular functions. Seven distinct phosphoinositide species require precise spatiotemporal control, which is regulated by specific phosphatidylinositol kinases and phosphatases. Here, we review one such family, the inositol polyphosphate 5-phosphatases, which comprise 10 mammalian enzymes that dephosphorylate the 5-position phosphate group from the inositol head group of PtdIns(4,5)P₂, PtdIns(3,5)P₂, and/or PtdIns(3,4,5)P₃. Despite overlapping substrate specificities, the 5-phosphatases play nonredundant roles, including in development, as demonstrated by murine and zebrafish knockout studies. Mutations in several 5-phosphatase family members are associated with multisystem developmental and congenital syndromes. Associations between 5-phosphatase gene variants and diabetes and metabolic syndrome, neurodegenerative disease, and in rare cases cancer, are also emerging. Here, we provide a comprehensive discussion of the latest advances in this field, including updates on disease modeling and mechanisms.