5 research outputs found

    The β-encapsulation cage of rearrangement hotspot (Rhs) effectors is required for type VI secretion

    No full text
    Bacteria deploy rearrangement hotspot (Rhs) proteins as toxic effectors against both prokaryotic and eukaryotic target cells. Rhs proteins are characterized by YD-peptide repeats, which fold into a large β-cage structure that encapsulates the C-terminal toxin domain. Here, we show that Rhs effectors are essential for type VI secretion system (T6SS) activity in Enterobacter cloacae (ECL). ECL rhs- mutants do not kill Escherichia coli target bacteria and are defective for T6SS-dependent export of hemolysin-coregulated protein (Hcp). The RhsA and RhsB effectors of ECL both contain Pro-Ala-Ala-Arg (PAAR) repeat domains, which bind the β-spike of trimeric valine-glycine repeat protein G (VgrG) and are important for T6SS activity in other bacteria. Truncated RhsA that retains the PAAR domain is capable of forming higher-order, thermostable complexes with VgrG, yet these assemblies fail to restore secretion activity to ∆rhsA ∆rhsB mutants. Full T6SS-1 activity requires Rhs that contains N-terminal transmembrane helices, the PAAR domain, and an intact β-cage. Although ∆rhsA ∆rhsB mutants do not kill target bacteria, time-lapse microscopy reveals that they assemble and fire T6SS contractile sheaths at ∼6% of the frequency of rhs+ cells. Therefore, Rhs proteins are not strictly required for T6SS assembly, although they greatly increase secretion efficiency. We propose that PAAR and the β-cage provide distinct structures that promote secretion. PAAR is clearly sufficient to stabilize trimeric VgrG, but efficient assembly of T6SS-1 also depends on an intact β-cage. Together, these domains enforce a quality control checkpoint to ensure that VgrG is loaded with toxic cargo before assembling the secretion apparatus

    Bringing an end to diabetes stigma and discrimination: an international consensus statement on evidence and recommendations

    No full text
    To accelerate an end to diabetes stigma and discrimination an international multi-disciplinary expert panel (N=51 members, 18 countries) conducted rapid reviews and participated in a three-round Delphi survey process. They achieved Consensus on 25 Statements of Evidence and 24 Statements of Recommendations. The Consensus is that diabetes stigma is driven primarily by blame, perceptions of burden/sickness, (in)visibility, and fear/disgust. People with diabetes often encounter sigma (negative social judgments, stereotypes, prejudice), which can adversely affect emotional, mental and physical health, self-care, access to optimal healthcare, and social and professional opportunities. Up to one-in-three experience discrimination (unfair and prejudicial treatment) due to diabetes, e.g., in healthcare, education and employment. Diabetes stigma and discrimination are harmful, unacceptable, unethical and counterproductive. Collective leadership is needed to pro-actively challenge, and bring an end to, diabetes stigma and discrimination. Consequently, the panel achieved unanimous consensus on a pledge to end diabetes stigma and discrimination
    corecore