HDAC6 mediates the acetylation of TRIM50

The E3 Ubiquitin ligase TRIM50 promotes the formation and clearance of aggresome-associated polyubiquitinated proteins through HDAC6 interaction, a tubulin specific deacetylase that regulates microtubule-dependent aggresome formation. In this report we showed that TRIM50 is a target of HDAC6 with Lys-372 as a critical residue for acetylation. We identified p300 and PCAF as two TRIM50 acetyltransferases and we further showed that a balance between ubiquitination and acetylation regulates TRIM50 degradatio

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management

Are there Local Differences in Support for Violent Radicalization? A Study on College Students in the Province of Quebec, Canada

Support for violent radicalization (VR) is a multidimensional phenomenon determined by individual, social, and contextual variables. However, how local contexts influence the configurations of risk and protective factors leading to the process of VR remains an open question. In line with a socioecological framework, this study aims to investigate local differences in support for VR and its associated risk factors (i.e., immigrant status, social adversity, depression, and collective identity) among college students in Quebec, a Canadian province with a variety of social and political contexts (i.e., Francophone Montreal, Quebec City, rural/suburban areas, and Anglophone communities). A total of 1765 college students (71% women; 73% aged between 16 and 21 years) completed an online survey. Mixed-effects models were implemented to test local differences in support for VR and its risk factors. Results showed that the association between social adversity (i.e., discrimination and exposure to violence) and support for VR varied by local context. Specifically, social adversity was a risk factor across all contexts but Quebec City. Although prevention programs may target common determinants of support for VR, they need to be tailored according to local realities, and in particular the level of social diversity and the relative prevalence of mainstream radical discourses

Factors Associated with Providers' Work Engagement and Burnout in Homeless Services: A Cross-national Study

Item does not contain fulltextThe complexity of homeless service users' characteristics and the contextual challenges faced by services can make the experience of working with people in homelessness stressful and can put providers' well-being at risk. In the current study, we investigated the association between service characteristics (i.e., the availability of training and supervision and the capability-fostering approach) and social service providers' work engagement and burnout. The study involved 497 social service providers working in homeless services in eight different European countries (62% women; mean age = 40.73, SD = 10.45) and was part of the Horizon 2020 European study "Homelessness as Unfairness (HOME_EU)." Using hierarchical linear modeling (HLM), findings showed that the availability of training and supervision were positively associated with providers' work engagement and negatively associated with burnout. However, results varied based on the perceived usefulness of the training and supervision provided within the service and the specific outcome considered. The most consistent finding was the association between the degree to which a service promotes users' capabilities and all the aspects of providers' well-being analyzed. Results are discussed in relation to their implications for how configuration of homeless services can promote social service providers' well-being and high-quality care

The E3-Ubiquitin Ligase TRIM50 Interacts with HDAC6 and p62, and Promotes the Sequestration and Clearance of Ubiquitinated Proteins into the Aggresome.

In this study we report that, in response to proteasome inhibition, the E3-Ubiquitin ligase TRIM50 localizes to and promotes the recruitment and aggregation of polyubiquitinated proteins to the aggresome. Using Hdac6-deficient mouse embryo fibroblasts (MEF) we show that this localization is mediated by the histone deacetylase 6, HDAC6. Whereas Trim50-deficient MEFs allow pinpointing that the TRIM50 ubiquitin-ligase regulates the clearance of polyubiquitinated proteins localized to the aggresome. Finally we demonstrate that TRIM50 colocalizes, interacts with and increases the level of p62, a multifunctional adaptor protein implicated in various cellular processes including the autophagy clearance of polyubiquitinated protein aggregates. We speculate that when the proteasome activity is impaired, TRIM50 fails to drive its substrates to the proteasome-mediated degradation, and promotes their storage in the aggresome for successive clearance