Telomere length is critical for chromosome stability that affects cell proliferation and survival. Telomere elongation by telomerase is inhibited by the telomeric protein, TRF1. Tankyrase-1 (TNKS1) poly(ADP-ribosyl)ates TRF1 and releases TRF1 from telomeres, thereby allowing access of telomerase to the telomeres. TNKS1-mediated poly(ADP-ribosyl)ation also appears to be crucial for regulating the mitotic cell cycle. In searching for proteins that interact with polo-like kinase-1 (Plk1) by using complex proteomics, we identified TNKS1 as a novel Plk1-binding protein. Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. Taken together, our results provide evidence of a novel molecular mechanism in which phosphorylation of TNKS1 by Plk1 may help regulate mitotic spindle assembly and promote telomeric chromatin maintenance.
Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signalresponsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination.Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses.Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.
Background: Globally, the incidence of allergic diseases is increasing along with cesarean delivery rates. Data regarding the association between cesarean delivery and allergic diseases are inconsistent. Here, we aimed to clarify the association between cesarean delivery and the development of asthma, atopic dermatitis, wheezing, and eczema. Methods: We used data from the Japan Environment and Children’s Study. The data included were those of 104,065 fetal records and their children. Information about the mode of delivery, asthma, atopic dermatitis, wheezing, and eczema was obtained from questionnaires and medical record transcripts. Multiple logistic regression analysis was used to assess the association between cesarean delivery and asthma, atopic dermatitis, wheezing, and eczema risk among infants at 1 year of age. Results: We included 74,639 subjects in this study, wherein 18.4% underwent cesarean deliveries. After adjusting for the perinatal, socioeconomic, and postnatal confounding factors, children born by cesarean delivery had no increased risk of developing asthma [95% confidence interval (CI) 0.84–1.08], atopic dermatitis (95% CI, 0.92–1.13), wheezing (95% CI, 0.94–1.04), or eczema (95% CI, 0.94–1.05). Conclusions: This nationwide cohort study found no association between cesarean delivery and asthma, atopic dermatitis, wheezing, and eczema among infants at 1 year of age. However, further studies are needed to evaluate whether cesarean delivery plays a role in the development of allergic diseases.
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