RNF13 mediates pH- and Ca-dependent regulation of lysosomal positioning.

Environmental factors such as extracellular pH (pH) and nutrition status affect lysosomal localization and autophagy, but how pH, intracellular pH (pH), and Ca regulate lysosome transport is not well understood. Here, we identify RNF13 as a key regulator of lysosomal positioning via pH- and Ca-dependent degradation of ARL8B. Ca-activated apoptosis-linked gene 2 (ALG-2) promotes retrograde lysosomal transport while increasing pH and decreasing lysosomal pH (pH).

Suzetrigine for moderate to severe acute pain.

Suzetrigine (VX-548), 2-pyridinecarboxamide, 4-[[[(2,3,4,5)-3-(3,4-difluoro-2-methoxyphenyl)tetrahydro-4,5-dimethyl-5-(trifluoromethyl)-2-furanyl]carbonyl]amino]-, or 4-[[(2,3,4,5)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carbonyl]amino]pyridine-2-carboxamide, is a selective voltage-gated sodium channel Na1.8 blocker that was recently approved by FDA as a non-opioid analgesic to treat moderate to severe acute pain. It has a molecular formula CHFNO and a molecular weight of 473.

Suppressing the Inflammatory Prostaglandin Signaling after Thrombotic Stroke Ameliorates Ischemic Brain Injury and Facilitates Poststroke Recovery.

Acute cerebral ischemia is a leading cause of death and disability, particularly among old adults. The narrow therapeutic window and risk of hemorrhagic transformation largely limit patient eligibility for the current treatment. The neuroinflammatory signaling pathway involving the prostaglandin E2 (PGE) receptor subtype EP2 has now been clarified to contribute to the secondary neurotoxicity following ischemic stroke.

Transmembrane E3 ligase RNF128 regulates N-glycosylation by promoting ribophorin I ubiquitination and degradation.

Ring finger protein 128 (RNF128) is a transmembrane E3 ubiquitin ligase mainly localized in the endoplasmic reticulum that is involved in various processes, including T cell anergy and tumor progression. However, the biological function of RNF128 in N-glycosylation remains unexplored. To investigate the functional role of RNF128, we used the proximity-directed biotin labeling method, and identified ribophorin I (RPN1) as a novel RNF128 substrate, demonstrating that RNF128 ubiquitinated RPN1 and promoted its degradation.

Microbiota Association and Profiling of Gingival Sulci and Root Canals of Teeth with Primary or Secondary/Persistent Endodontic Infections.

Introduction: Microbiota associated with primary endodontic infection (PEI) and secondary/persistent endodontic infection (SPEI) must be characterized to elucidate pathogenesis in apical periodontitis and bacterial biomarkers identified for diagnostic and therapeutic applications.

Methods: This study analyzed the microbial community profiles of root canals and gingival sulci (sulcus-E) for teeth with PEI (n = 10) or SPEI (n = 10), using the Illumina MiSeq platform. Bacterial samples from gingival sulci (sulcus-C) of healthy contralateral teeth served as controls.

Endodontic Microsurgery Outcomes over 10 Years and Associated Prognostic Factors: A Retrospective Cohort Study.

Introduction: This retrospective cohort study aimed to evaluate long-term healing outcomes (10-17.5 years) after contemporary endodontic microsurgery (EMS) and identify the associated prognostic factors.

Methods: Clinical and radiographic data of an EMS cohort (2006-2013) from the electronic database of the dental hospital were reviewed retrospectively by 2 independent examiners to determine their survival and healing outcomes, and potential prognostic factors were analyzed by Cox proportional hazards regression and logistic regression (α = 0.

FAM19A5l Affects Mustard Oil-Induced Peripheral Nociception in Zebrafish.

Family with sequence similarity 19 (chemokine (C-C motif)-like) member A5 (FAM19A5) is a chemokine-like secretory protein recently identified as involved in the regulation of osteoclast formation, post-injury neointima formation, and depression. Although roles for FAM19A5 have been described in nervous system development and psychiatric disorders, its role in the nervous system remains poorly understood. Here, we analyzed the evolutionary history of FAM19A genes in vertebrates and identified FAM19A5l, a paralogous zebrafish gene originating from a common ancestral FAM19A5 gene.

The unique expression profile of FAM19A1 in the mouse brain and its association with hyperactivity, long-term memory and fear acquisition.

Neurodevelopment and mature brain function are spatiotemporally regulated by various cytokines and chemokines. The chemokine-like neuropeptide FAM19A1 is a member of family with sequence similarity 19 (FAM19), which is predominantly expressed in the brain. Its highly conserved amino acid sequence among vertebrates suggests that FAM19A1 may play important physiological roles in neurodevelopment and brain function.

Serum FAM19A5 in neuromyelitis optica spectrum disorders: Can it be a new biomarker representing clinical status?

Background: Neuromyelitis optica spectrum disorder (NMOSD) targets astrocytes and elevates the levels of astrocyte-injury markers during attacks. FAM19A5, involved in reactive gliosis, is secreted by reactive astrocytes following central nervous system (CNS) damage.

Objective: To investigate the significance of serum FAM19A5 in patients with NMOSD.

FAM19A5 Expression During Embryogenesis and in the Adult Traumatic Brain of Knock-in Mice.

FAM19A5 is a secretory protein that is predominantly expressed in the brain. Although the gene has been found to be associated with neurological and/or psychiatric diseases, only limited information is available on its function in the brain. Using knock-in mice, we determined the expression pattern of FAM19A5 in developing and adult brains and identified cell types that express FAM19A5 in naïve and traumatic brain injury (TBI)-induced brains.

The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins.

The E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) is known to be involved in intracellular vesicular trafficking, but its role in the early secretory pathway between the endoplasmic reticulum (ER) and Golgi compartments is largely unknown. Human ER-Golgi intermediate compartment protein 2 (ERGIC2) and ERGIC3 are orthologs of Erv41 and Erv46 in yeast, proteins that form a heteromeric complex, cycle between the ER and Golgi, and function as cargo receptors in both anterograde and retrograde protein trafficking. Here, we report that MARCH2 directs ubiquitination and subsequent degradation of ERGIC3 and that MARCH2 depletion increases endogenous ERGIC3 levels.

RNF8 mediates NONO degradation following UV-induced DNA damage to properly terminate ATR-CHK1 checkpoint signaling.

RNF8 plays a critical role in DNA damage response (DDR) to initiate ubiquitination-dependent signaling. To better characterize the role of RNF8 in UV-induced DDR, we searched for novel substrates of RNF8 and identified NONO as one intriguing substrate. We found that: (i) RNF8 ubiquitinates NONO and (ii) UV radiation triggers NONO ubiquitination and its subsequent degradation.

β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin.

Dystroglycan is a ubiquitous membrane protein that functions as a mechanical connection between the extracellular matrix and cytoskeleton. In skeletal muscle, dystroglycan plays an indispensable role in regulating muscle regeneration; a malfunction in dystroglycan is associated with muscular dystrophy. The regulation of dystroglycan stability is poorly understood.

FAM19A5, a brain-specific chemokine, inhibits RANKL-induced osteoclast formation through formyl peptide receptor 2.

Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue.

RNF167 targets Arl8B for degradation to regulate lysosome positioning and endocytic trafficking.

The protease-associated (PA) domain-containing E3 ubiquitin ligases are transmembrane proteins located in intracellular organelles such as the endoplasmic reticulum, endosomes, or lysosomes. The functional roles of these ubiquitin ligases are not well defined. To understand the function of E3 ubiquitin ligases, identification of their substrates is of critical importance.

CC2D1A and CC2D1B regulate degradation and signaling of EGFR and TLR4.

Signaling through many transmembrane receptors is terminated by their sorting to the intraluminal vesicles (ILVs) of multivescular bodies (MVBs) and subsequent lysosomal degradation. ILV formation requires the endosomal sorting complex required for transport (ESCRT) machinery. CC2D1A and CC2D1B interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex, however, their roles in receptor degradation and signaling are poorly defined.

Prevertebrate Local Gene Duplication Facilitated Expansion of the Neuropeptide GPCR Superfamily.

In humans, numerous genes encode neuropeptides that comprise a superfamily of more than 70 genes in approximately 30 families and act mainly through rhodopsin-like G protein-coupled receptors (GPCRs). Two rounds of whole-genome duplication (2R WGD) during early vertebrate evolution greatly contributed to proliferation within gene families; however, the mechanisms underlying the initial emergence and diversification of these gene families before 2R WGD are largely unknown. In this study, we analyzed 25 vertebrate rhodopsin-like neuropeptide GPCR families and their cognate peptides using phylogeny, synteny, and localization of these genes on reconstructed vertebrate ancestral chromosomes (VACs).

A novel glucagon-related peptide (GCRP) and its receptor GCRPR account for coevolution of their family members in vertebrates.

The glucagon (GCG) peptide family consists of GCG, glucagon-like peptide 1 (GLP1), and GLP2, which are derived from a common GCG precursor, and the glucose-dependent insulinotropic polypeptide (GIP). These peptides interact with cognate receptors, GCGR, GLP1R, GLP2R, and GIPR, which belong to the secretin-like G protein-coupled receptor (GPCR) family. We used bioinformatics to identify genes encoding a novel GCG-related peptide (GCRP) and its cognate receptor, GCRPR.

Spatiotemporal expression and functional implication of CXCL14 in the developing mice cerebellum.

Cerebellar granule neurons migrate from the external granule cell layer (EGL) to the internal granule cell layer (IGL) during postnatal morphogenesis. This migration process through 4 different layers is a complex mechanism which is highly regulated by many secreted proteins. Although chemokines are well-known peptides that trigger cell migration, but with the exception of CXCL12, which is responsible for prenatal EGL formation, their functions have not been thoroughly studied in granule cell migration.

Molecular Coevolution of Neuropeptides Gonadotropin-Releasing Hormone and Kisspeptin with their Cognate G Protein-Coupled Receptors.

The neuropeptides gonadotropin-releasing hormone (GnRH) and kisspeptin (KiSS), and their receptors gonadotropin-releasing hormone receptor (GnRHR) and kisspeptin receptor (KiSSR) play key roles in vertebrate reproduction. Multiple paralogous isoforms of these genes have been identified in various vertebrate species. Two rounds of genome duplication in early vertebrates likely contributed to the generation of these paralogous genes.

Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important roles in insulin secretion through their receptors, GLP1R and GIPR. Although GLP-1 and GIP are attractive candidates for treatment of type 2 diabetes and obesity, little is known regarding the molecular interaction of these peptides with the heptahelical core domain of their receptors. These core domains are important not only for specific ligand binding but also for ligand-induced receptor activation.