RanBP2 Modulates Cox11 and Hexokinase I Activities and Haploinsufficiency of RanBP2 Causes Deficits in Glucose Metabolism

The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(−/−) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/−) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies

Ran-dependent docking of importin-β to RanBP2/Nup358 filaments is essential for protein import and cell viability

RanBP2 captures RanGTP–importin-β complexes at cytoplasmic fibrils to ensure adequate classical NLS–mediated protein import and cell viability

The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity

Direct interaction between the catalytic domain of Epac1 and the nuclear pore component RanBP2 blocks Epac1 catalytic activity and downstream cAMP signaling

Genomic organization, expression, and localization of murine Ran-binding protein 2 (RanBP2) gene.

Item does not contain fulltextThe Ran-binding protein 2 (RanBP2) is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. There are no orthologs of the RanBP2 gene in yeast and Drosophila genomes. In humans, this bona fide gene is partially duplicated in a RanBP2 gene cluster and lies in a hot spot for recombination on Chromosome (Chr) 2q. This genetic heterogeneity renders further significance of this genomic region in human disease due to its possible involvement in genetically linked disorders such as juvenile nephronophthisis, congenital hepatic fibrosis, and chorioretinal dysplasia. Structure-function studies on bovine RanBP2 indicate that this protein is involved in integrating nucleocytoplasmic transport pathways with protein biogenesis such as production of functional opsin. To gain further insight into the complex functions of RanBP2 in the development and function of the neuroretina and other tissues, and proceed towards the functional analysis of RanBP2 and its molecular partners in vivo, we have determined the complete genomic organization of the murine RanBP2 gene. The gene consists of 29 exons spread over 50 kb and contains a mega-exon of 4663 bp that encompasses the variable Zn-finger-rich domain of RanBP2. This may account, in part, for a predisposition of recombination of this locus and variability of the number of Zn-fingers across mammalian species. The RanBP2 promoter contains tissue-specific elements. A CpG island encompasses this region up to the first intron, making RanBP2 gene expression susceptible of epigenetic regulation. This murine RanBP2 transcript has a tissue-restricted expression profile, and the conceptual protein is 82% identical to human RanBP2. The gene maps to mouse Chr 10, 30 cM proximal of the centromere

Prolyl-hydroxylase inhibitor-induced regeneration of alveolar bone and soft tissue in a mouse model of periodontitis through metabolic reprogramming.

Bone injuries and fractures reliably heal through a process of regeneration with restoration to original structure and function when the gap between adjacent sides of a fracture site is small. However, when there is significant volumetric loss of bone, bone regeneration usually does not occur. In the present studies, we explore a particular case of volumetric bone loss in a mouse model of human periodontal disease (PD) in which alveolar bone surrounding teeth is permanently lost and not replaced. This model employs the placement a ligature around the upper second molar for 10 days leading to inflammation and bone breakdown and faithfully replicates the bacterially-induced inflammatory etiology of human PD to induce bone degeneration. After ligature removal, mice are treated with a timed-release formulation of a small molecule inhibitor of prolylhydroxylases (PHDi; 1,4-DPCA) previously shown to induce epimorphic regeneration of soft tissue in non-regenerating mice. This PHDi induces high expression of HIF-1α and is able to shift the metabolic state from OXPHOS to aerobic glycolysis, an energetic state used by stem cells and embryonic tissue. This regenerative response was completely blocked by siHIF1a. In these studies, we show that timed-release 1,4-DPCA rapidly and completely restores PD-affected bone and soft tissue with normal anatomic fidelity and with increased stem cell markers due to site-specific stem cell migration and/or de-differentiation of local tissue, periodontal ligament (PDL) cell proliferation, and increased vascularization. In-vitro studies using gingival tissue show that 1,4-DPCA indeed induces de-differentiation and the expression of stem cell markers but does not exclude the role of migrating stem cells. Evidence of metabolic reprogramming is seen by the expression of not only HIF-1a, its gene targets, and resultant de-differentiation markers, but also the metabolic genes Glut-1, Gapdh, Pdk1, Pgk1 and Ldh-a in jaw periodontal tissue

Саркома из фолликулярных дендритных клеток: клинические наблюдения и данные литературы

The article is devoted to the diagnosis and treatment of an extremely rare tumor – a sarcoma from follicular dendritic cells with extranodal lesion in the region of the head and neck. These tumors are characterized by a high potential for metastasis and recurrence. Difficulties in choosing the optimal treatment tactics are associated with a small number of observations. Surgical, radiotherapeutics and chemotherapy methods are used. The literature data and the description of 2 own clinical observations of the sarcoma from follicular dendritic cells (with the involvement of the maxillary sinus and the nasal cavity) are presented. Treatment (surgery followed by radiotherapy) was successful. The appointment of adjuvant therapy improves the results of treatment in comparison with the surgical method alone.Статья посвящена вопросам диагностики и лечения крайне редкой опухоли – саркомы из фолликулярных дендритных клеток с экстранодальным поражением области головы и шеи. Эти опухоли характеризуются высоким потенциалом метастазирования и рецидивирования. Оптимальная тактика лечения в данный момент остается предметом обсуждения по причине редкости заболевания; используются хирургический, лучевой и медикаментозный методы. Представлены данные литературы и описание 2 собственных клинических наблюдений – с поражением верхнечелюстной пазухи и полости носа. Лечение (операция и последующая лучевая терапия) было успешным. Исход хирургического лечения при проведении последующей адъювантной лучевой терапии оказался лучшим, чем без ее проведения

Follicular dendritic cell sarcoma: a report of cases and a literature review

The article is devoted to the diagnosis and treatment of an extremely rare tumor – a sarcoma from follicular dendritic cells with extranodal lesion in the region of the head and neck. These tumors are characterized by a high potential for metastasis and recurrence. Difficulties in choosing the optimal treatment tactics are associated with a small number of observations. Surgical, radiotherapeutics and chemotherapy methods are used. The literature data and the description of 2 own clinical observations of the sarcoma from follicular dendritic cells (with the involvement of the maxillary sinus and the nasal cavity) are presented. Treatment (surgery followed by radiotherapy) was successful. The appointment of adjuvant therapy improves the results of treatment in comparison with the surgical method alone