USP13 controls the stability of Aurora B impacting progression through the cell cycle.

Aurora B kinase plays essential roles in mitosis. Its protein levels increase before the onset of mitosis and sharply decrease during mitosis exit. The latter decrease is due to a balance between the actions of the E3 ubiquitin ligase anaphase-promoting complex or cyclosome (activated by the Cdh1 adapter), and the deubiquitinating enzyme USP35. Aurora B also executes important functions in interphase. Abnormal modulation of Aurora B in interphase leads to cell cycle defects often linked to aberrant chromosomal condensation and segregation. Very little is however known about how Aurora B levels are regulated in interphase. Here we found that USP13-associates with and stabilizes Aurora B in cells, especially before their entry into mitosis. In order for USP13 to exert its stabilizing effect on Aurora B, their association is promoted by the Aurora B-mediated phosphorylation of USP13 at Serine 114. We also present evidence that USP13 instigates Aurora B deubiquitination and/or protect it from degradation in a non-catalytic manner. In addition, we report that genetic or chemical modulation of the cellular levels/activity of USP13 affects unperturbed cell-cycle progression. Overall our study unveils the molecular and cellular connections of the USP13-Aurora B axis, which potentially participates in the rewiring of the cell cycle happening in cancer cells.

Safety of reduced antigen content diphtheria-tetanus-acellular pertussis vaccine when administered during pregnancy as part of the maternal immunization program in Brazil: a single center, observational, retrospective, cohort study.

Reduced antigen diphtheria-tetanus-acellular pertussis (Tdap) vaccination is included in the maternal immunization program in Brazil since September 2014. We investigated associations between maternal Tdap vaccination and pregnancy-related adverse events (AEs) (gestational diabetes, pregnancy-related hypertension, and pregnancy hemorrhage) and neonatal AEs of interest (preterm birth and small for gestational age). This descriptive, observational, retrospective, single-center study in Brazil (NCT02757950) compared data from medical charts of 1203 pregnant women who received Tdap as part of the maternal immunization program and delivered between May 2015 and February 2017 (exposed cohort) and 1259 unvaccinated women who delivered between September 2012 and August 2014 (unexposed cohort). Index dates were defined as the time of vaccination (27-39 gestational weeks; exposed cohort) or 27 gestational weeks (unexposed cohort). Cumulative incidences were calculated as the number of women with each event between index and delivery dates divided by the total number of women with vaccination date available in the exposed cohort (N = 1199) or the total number of women in the unexposed cohort (N = 1259). Cumulative incidences per 1000 persons were 8.34 versus 17.47 for gestational diabetes, 9.17 versus 24.62 for pregnancy-related hypertension, 3.34 versus 15.09 for pregnancy hemorrhage, 53.38 versus 96.11 for preterm birth, and 57.55 versus 49.25 for small for gestational age in the exposed versus unexposed cohorts. No increased risk of pregnancy-related AEs or neonatal AEs of interest was found following maternal vaccination with Tdap. These results should be interpreted cautiously due to limitations inherent to retrospective observational studies.

The structure of TAX1BP1 UBZ1+2 provides insight into target specificity and adaptability.

TAX1BP1 is a novel ubiquitin-binding adaptor protein involved in the negative regulation of the NF-kappaB transcription factor, which is a key player in inflammatory responses, immunity and tumorigenesis. TAX1BP1 recruits A20 to the ubiquitinated signaling proteins TRAF6 and RIP1, leading to their A20-mediated deubiquitination and the disruption of IL-1-induced and TNF-induced NF-kappaB signaling, respectively. The two zinc fingers localized at its C-terminus function as novel ubiquitin-binding domains (UBZ, ubiquitin-binding zinc finger). Here we present for the first time both the solution and crystal structures of two classical UBZ domains in tandem within the human TAX1BP1. The relative orientation of the two domains is slightly different in the X-ray structure with respect to the NMR structure, indicating some degree of conformational flexibility, which is rationalized by NMR relaxation data. The observed degree of flexibility and stability between the two UBZ domains might have consequences on the recognition mechanism of interacting partners.

Multimeric and differential binding of CIN85/CD2AP with two atypical proline-rich sequences from CD2 and Cbl-b*.

The CD2AP (CD2-associated protein) and CIN85 (Cbl-interacting protein of 85 kDa) adaptor proteins each employ three Src homology 3 (SH3) domains to cluster protein partners and ensure efficient signal transduction and down-regulation of tyrosine kinase receptors. Using NMR, isothermal titration calorimetry and small-angle X-ray scattering methods, we have characterized several binding modes of the N-terminal SH3 domain (SH3A) of CD2AP and CIN85 with two natural atypical proline-rich regions in CD2 (cluster of differentiation 2) and Cbl-b (Casitas B-lineage lymphoma), and compared these data with previous studies and published crystal structures. Our experiments show that the CD2AP-SH3A domain forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b. Like CD2AP, the CIN85-SH3A domain forms a type II complex with CD2, but a trimeric complex with Cbl-b, whereby the type I and II interactions take place at the same time. Together, these results explain how multiple interactions among similar SH3 domains and ligands produce a high degree of diversity in tyrosine kinase, cell adhesion or T-cell signaling pathways.