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Age-related hearing loss (ARHL) is a prevalent and complex disorder in older adults. Guo et al. identify human antigen R as a regulator of ARHL in aged mice and demonstrate that cochlear human antigen R overexpression alleviates ARHL, highlighting it as a therapeutic target for the condition.

Human antigen R (HuR) is an RNA binding protein that promotes mRNA stability. Here the authors show that HuR represses adipogenesis in white and brown adipose tissue by stabilizing Insig1 and other targets.

Mutations in the RNA component TERC can cause telomerase dysfunction but the underlying mechanisms are largely unknown. Here, the authors show that RNA-binding protein HuR regulates telomerase function by enhancing the methylation of TERC, which is impaired by several disease-relevant TERC mutations.

Huang et al. identify IGF2BPs as an additional class of N⁶-methyladenosine (m⁶A) reader proteins. They find that IGF2BPs selectively bind to m⁶A-containing mRNAs and promote their stability.

Poly(A)-Binding Protein Cytoplasmic 1 (PABPC1) is a crucial component of stress granules. Here, the authors show that PABPC1 undergoes SUMOylation in response to cellular stress, enhancing the stability of mitophagy-related gene transcripts to promote cancer cell survival.

DNA methylation is an important regulatory process and is essential for correct development and physiology. Here the authors show the long non-coding RNA H19regulates methylation by binding and inhibiting S-adenosylhomocysteine hydrolase.

The relevance of post-translational modifications in pancreatic cancer remains insufficiently explored. Here, the authors report that ZDHHC20-mediated S-Palmitoylation of the m6A reader YTHDF3 stabilizes MYC mRNA to promote the progression of KRAS-mutant pancreatic cancer.

By highlighting recent advancements in the understanding of circRNA-protein interactions, this review discusses their implications in cancer therapy and drug resistance mechanisms.

Serine metabolism is essential for leukemogenesis and stemness in acute myeloid leukemia (AML). Here the authors show that targeting IGF2BP3 disrupts the serine synthesis pathway in AML cells in an RNA N⁶-Methyladenosine modification dependent manner, sensitizing AML cells to serine and glycine deprivation.

The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.

The authors identify a human cytomegalovirus long non-coding RNA, RNA4.9, that interacts with cGAS and prevents its activation in the nucleus, thereby suppressing virus-induced IFN expression and antiviral activity.

Sun Hur and colleagues examine the mechanism of Aire protein function underlying peripheral tissue antigen gene expression in thymic mTECs. They show that Aire condensates assemble on enhancers that are subject to intricate regulatory mechanisms, ensuring tight coordination of Aire CARD polymerization with genomic target recognition.

The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.

The antiviral dsRNA sensor PKR is regulated by PACT. This paper shows how PACT prevents aberrant PKR activation by endogenous dsRNAs like Alu. PACT disrupts PKR’s dsRNA scanning without blocking its binding, resetting its activation threshold to tolerate cellular dsRNA and preserve homeostasis.

The activation of stress kinases, such as p38 MAPK, is believed to be detrimental to normal cellular processes. However, Umut Ozcan and his colleagues now show that p38 MAPK is actually beneficial, as in mice it increases the mRNA stability and nuclear localization of Xbp1s, a crucial factor in resolving endoplasmic reticulum stress and improving glucose homeostasis. These results suggest a possible indirect way of targeting XBP1s in the treatment of type 2 diabetes.

The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.

Long noncoding RNAs have been shown to play a role in cardiovascular disease. Here, the authors identify a lncRNA named CCRR, whose downregulation in failing hearts causes cardiac conduction disturbances by altering the endocytic trafficking of Cx43.

The blood ApoM-S1P complex regulates vascular functions, but its role in neurogenic niches remains unclear. Here, the authors show that the blood ApoM-S1P complex preserves V-SVZ homeostasis and protects against early features of Alzheimer’s disease.

Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.

Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) shuttles between the nucleus and cytoplasm to regulate gene expression and RNA metabolism and its low complexity (LC) C-terminal domain facilitates liquid–liquid phase separation and amyloid aggregation. Here, the authors present the cryo-EM structure of amyloid fibrils formed by the hnRNPA1 LC domain, which reveals that the hnRNPA1 nuclear localization sequence forms the fibril core, and they discuss how ALS-causing mutations affect fibril stability.

Enolase 1 (ENO1) is a critical glycolytic enzyme that plays essential roles in pathological activities. Here, Sun, Suo, Zhang, Shen et al. reveal the nonmetabolic function of ENO1 in liver cancer, where ENO1 promotes YAP1 mRNA translation to activate arachidonic acid metabolism thus promoting cancer growth.

In addition to its role in suppressing MDA5 and PKR activation, ADAR1 is a negative regulator of ZPB1-mediated apoptosis and necroptosis, providing insights into the pathology of Aicardi–Goutières syndrome.

Nucleobase modifications are prevalent in eukaryotic mRNA and are broadly required for post-transcriptional gene regulation. The most studied mRNA modification is N⁶-methyladenosine (m⁶A), yet various other modifications are now being identified and studied. This Review discusses the emerging mechanisms and roles of these non-m⁶A modifications.

RIG-I protein recognizes viral duplex RNA with a 5′-triphosphate group, activating innate immune responses; a crystal structure of its tetrameric CARD signalling domain reveals that non-covalently linked ubiquitin chains stabilize the tetramer in a ‘lock-washer’ structure that serves as a signalling platform for the recruitment and activation of MAVS.

FOXP3 uses the forkhead domain to form a higher-order multimer after binding to T_nG repeat microsatellites.

Hypertension is the leading risk factor for cardiovascular disease, which represents the top cause of morbidity and mortality worldwide. Here, the authors show deletion of endothelial Sp1 and Sp3 leads to a disruption in endothelium-dependent vasodilation and the onset of hypertension, which abolishes the beneficial actions of captopril.

Zhang et al. report that the lncRNA H19 stabilizes dystrophin by competing with the ubiquitin E3 ligase TRIM63 for association with dystrophin, thereby alleviating muscular dystrophies.

Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.