Identification of PP2A-B55 targets uncovers regulation of emerin during nuclear envelope reassembly in Drosophila.

Mitotic exit requires the dephosphorylation of many proteins whose phosphorylation was needed for mitosis. Protein phosphatase 2A with its B55 regulatory subunit (PP2A-B55) promotes this transition. However, the events and substrates that it regulates are incompletely understood. We used proteomic approaches in Drosophila to identify proteins that interact with and are dephosphorylated by PP2A-B55. Among several candidates, we identified emerin (otefin in Drosophila). Emerin resides in the inner nuclear membrane and interacts with the DNA-binding protein barrier-to-autointegration factor (BAF) via a LEM domain. We found that the phosphorylation of emerin at Ser50 and Ser54 near its LEM domain negatively regulates its association with BAF, lamin and additional emerin in mitosis. We show that dephosphorylation of emerin at these sites by PP2A-B55 determines the timing of nuclear envelope reformation. Genetic experiments indicate that this regulation is required during embryonic development. Phosphoregulation of the emerin-BAF complex formation by PP2A-B55 appears as a key event of mitotic exit that is likely conserved across species.

HP1γ Prevents Activation of the cGAS/STING Pathway by Preserving Nuclear Envelope and Genomic Integrity in Colon Adenocarcinoma Cells.

Chronic inflammatory processes in the intestine result in serious conditions such as inflammatory bowel disease (IBD) and cancer. An increased detection of cytoplasmic DNA sensors has been reported in the IBD colon mucosa, suggesting their contribution in mucosal inflammation. Yet, the mechanisms altering DNA homeostasis and triggering the activation of DNA sensors remain poorly understood. In this study, we show that the epigenetic regulator HP1γ plays a role in preserving nuclear envelope and genomic integrity in enterocytic cells, thereby protecting against the presence of cytoplasmic DNA. Accordingly, HP1 loss of function led to the increased detection of cGAS/STING, a cytoplasmic DNA sensor that triggers inflammation. Thus, in addition to its role as a transcriptional silencer, HP1γ may also exert anti-inflammatory properties by preventing the activation of the endogenous cytoplasmic DNA response in the gut epithelium.

Bone involvement in males with Kallmann disease.

BACKGROUND: Kallmann syndrome (KS) is a rare genetic condition characterized by congenital early-onset hypogonadotropic hypogonadism and anosmia or hyposmia. Male subjects are more frequently affected and present absent/delayed puberty, low testosterone levels with higher risk for osteoporosis. Therefore, to maintain normal levels of sex steroids and prevent bone loss, male KS needs life-long hormonal replacement therapy (HRT). AIMS: The objective of our study is to assess bone involvement in subjects with KS currently treated with HRT. METHODS: In our retrospective study, we analyzed data from medical records of patients with KS treated with HRT (either gonadotropins or testosterone preparations), including clinical history, biochemical parameters, and the following outcome measures: the bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total body less head (TBLH); and the Vertebral Fracture Assessment (VFA) by Dual Energy X-ray Absorptiometry (DXA). RESULTS: Clinical and instrumental data of 32 patients with KS were evaluated; their mean age was 30.32 (± 10.09) years, their mean body mass index (BMI) was 25.71 (± 3.23) kg/m(2). Four patients (12.5%) had a LS BMD Z score below the expected range for age. Five patients had vertebral deformities observed at VFA. Duration of HRT was related to bone health parameters: BMD at all measured sites were higher in patients receiving adequate HRT for more than 2 years compared with the patients treated for less than 6 months. A deficient vitamin D status was found in 43% of cases and it was prevalent in patients with shorter HRT. DISCUSSION AND CONCLUSION: Early starting and adequate duration of HRT are related to bone health parameters in patients with congenital hypogonadotropic hypogonadism due to KS. Restoring vitamin D sufficiency might also be advisable in this condition.

Bone quality and bone strength: benefits of the bone-forming approach.

The ability of bone to resist fracture depends on the intrinsic properties of the materials that comprise the bone matrix mineralization, the amount of bone (i.e. mass), and the spatial distribution of the bone mass (i.e. microarchitecture). Antiresorptive agents may prevent the decay of cancellous bone and cortical thinning, with no improvement of bone microstructure, leading to a partial correction of the principal bone quality defect in osteoporosis, the disruption of trabecular microarchitecture. Anabolic agents promote bone formation at both trabecular and endocortical surfaces, resulting in an increase of cancellous bone volume and cortical thickness. The improvement of cortical bone strength may be limited by an increase in cortical porosity. strontium ranelate improves trabecular network and cortical thickness that will contribute to anti-fracture efficacy at both vertebral and non-vertebral sites. The results of clinical and experimental studies are consistent with the mode of action of strontium involving dissociation between bone formation and resorption leading to a stimulation both trabecular and cortical bone formation without increasing cortical porosity.