Life Science Alliance最新文献

The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as upstream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute to ∼30% of human solid tumours, including lung adenocarcinoma, pancreatic, and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. However, the precise signalling cascades these mutations affect are poorly understood. Here, APEX2 proximity labelling was used to profile the molecular environment of WT, G12D, G13D, and Q61H-activating KRAS mutants under starvation and stimulation conditions. Through quantitative proteomics, we demonstrate the presence of known KRAS interactors, including ARAF and LZTR1, which are differentially captured by WT and KRAS mutants. Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.

Immunotherapy has proven to be a boon for patients battling metastatic melanoma, significantly improving their clinical condition and overall quality of life. A compelling link between the composition of the gut microbiome and the efficacy of immunotherapy has been established in both animal models and human patients. However, the precise biological mechanisms by which gut microbes influence treatment outcomes remain poorly understood. Using a robust dataset of 680 fecal metagenomes from melanoma patients, a detailed catalog of metagenome-assembled genomes (MAGs) was constructed to explore the compositional and functional properties of the gut microbiome. Our study uncovered significant findings that deepen the understanding of the intricate relationship between gut microbes and the efficacy of melanoma immunotherapy. In particular, we discovered the specific metagenomic profile of patients with favorable treatment outcomes, characterized by a prevalence of MAGs with increased overall metabolic potential and proficiency in polysaccharide utilization, along with those responsible for cobalamin and amino acid production. Furthermore, our investigation of the biosynthetic pathways of short-chain fatty acids, known for their immunomodulatory role, revealed a differential abundance of these pathways among the specific MAGs. Among others, the cobalamin-dependent Wood-Ljungdahl pathway of acetate synthesis was directly associated with responsiveness to melanoma immunotherapy.

Myocardial lipid metabolism is critical to normal heart function, whereas altered lipid regulation has been linked to cardiac diseases including cardiomyopathies. Genetic variants in the JPH2 gene can cause hypertrophic cardiomyopathy (HCM) and, in some cases, dilated cardiomyopathy (DCM). In this study, we tested the hypothesis that JPH2 variants identified in patients with HCM and DCM, respectively, cause distinct alterations in myocardial lipid profiles. Echocardiography revealed clinically significant cardiac dysfunction in both knock-in mouse models of cardiomyopathy. Unbiased myocardial lipidomic analysis demonstrated significantly reduced levels of total unsaturated fatty acids, ceramides, and various phospholipids in both mice with HCM and DCM, suggesting a common metabolic alteration in both models. On the contrary, significantly increased di- and triglycerides, and decreased co-enzyme were only found in mice with HCM. Moreover, mice with DCM uniquely exhibited elevated levels of cholesterol ester. Further in-depth analysis revealed significantly altered metabolites from all the lipid classes with either similar or opposing trends in JPH2 mutant mice with HCM or DCM. Together, these studies revealed, for the first time, unique alterations in the cardiac lipid composition-including distinct increases in neutral lipids and decreases in polar membrane lipids-in mice with HCM and DCM were caused by distinct JPH2 variants. These studies may aid the development of novel biomarkers or therapeutics for these inherited disorders.

The ubiquitin-specific protease (USP) family of deubiquitinases (DUBs) controls cellular ubiquitin-dependent signaling events. This generates therapeutic potential, with active-site inhibitors in preclinical and clinical studies. Understanding of the USP active site is primarily guided by USP7 data, where the catalytic triad consists of cysteine, histidine, and a third residue (third critical residue), which polarizes the histidine through a hydrogen bond. A conserved aspartate (fourth critical residue) is directly adjacent to this third critical residue. Although both critical residues accommodate catalysis in USP2, these residues have not been comprehensively investigated in other USPs. Here, we quantitatively investigate their roles in five USPs. Although USP7 relies on the third critical residue for catalysis, this residue is dispensable in USP1, USP15, USP40, and USP48, where the fourth critical residue is vital instead. Furthermore, these residues vary in importance for nucleophilic attack. The diverging catalytic mechanisms of USP1 and USP7 are independent of substrate and retained in cells for USP1. This unexpected variety of catalytic mechanisms in this well-conserved protein family may generate opportunities for selective targeting of individual USPs.