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Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM⁺ HDL contained S1P, whereas ApoM⁻ HDL did not. Moreover, HDL in Apom⁻/⁻ mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM⁺ HDL induced S1P₁ receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM⁻ HDL did not. Importantly, lack of S1P in the HDL fraction of Apom⁻/⁻ mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P₁ receptor on endothelial cells, is a vasculoprotective constituent of HDL.

Varicella zoster virus (VZV) is a human pathogen from the α-subfamily of herpesviruses. Here, the crystal structure of the VZV Orf24-Orf27 complex is described, representing the essential viral core nuclear egress complex (NEC) that orchestrates the egress of the preassembled capsids from the nucleus. While previous studies have primarily emphasized the finding that the architecture of core NEC complexes is highly conserved among herpesviruses, the present report focusses on subfamily-specific structural and functional features that help explain the differences in the autologous versus nonautologous interaction patterns observed for NEC formation across herpesviruses. CoIP and confocal imaging data show that Orf24-Orf27 complex formation displays some promiscuity in a herpesvirus subfamily-restricted manner. At the same time, analysis of the NEC formation thermodynamic parameters of three prototypical α-, β- and γ-herpesviruses, i.e. VZV, human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) reveals highly similar binding affinities for the autologous interaction with some specific differences in the enthalpy and entropy terms. Computational alanine scanning and structural comparisons highlight intermolecular interactions shared among α-herpesviruses that are clearly distinct from those seen in β- and γ-herpesviruses. Combined, these data allow to explain the distinct properties of specificity and permissivity so far observed in herpesviral NEC interactions. These findings might prove highly valuable when attempting to target multiple herpesvirus core NECs with selective or broad-acting drug candidates. Competing Interest Statement The authors have declared no competing interest.

Salmonella invasion is mediated by a concerted action of the Salmonella pathogenicity island 4 (SPI4)-encoded type one secretion system (T1SS) and the SPI1-encoded type three secretion system (T3SS-1). The SPI4-encoded T1SS establishes the first contact to the host membrane. It consists of five proteins (SiiABCDF) that secrete the giant adhesin SiiE. The exact mechanism by which the T1SS enables host cell recognition remains unclear. Here, we investigated structure-function relationships in SiiA, a non-canonical T1SS subunit located at the inner membrane (IM). We observe that SiiA consists of a membrane domain, an intrinsically disordered periplasmic linker region and a folded globular periplasmic domain (SiiA-PD). The crystal structure of SiiA-PD shows homology to that of MotB-PD and other peptidoglycan (PG)-binding domains. Indeed, SiiA-PD binds PG in vitro albeit at an acidic pH, only, whereas MotB-PD binds PG from pH 5.8 to 8. Mutation of Arg162 in SiiA impedes PG binding and reduces Salmonella invasion efficacy of polarized epithelial cells. SiiA forms a complex with SiiB at the IM, and the SiiA-MotB homology is likely paralleled by a SiiB-MotA homology. We show that, in addition to PG binding, the SiiAB complex translocates protons across the IM. Substituting Asp13 in SiiA impairs proton translocation. Overall, SiiA displays many properties previously observed in MotB. However, whereas the MotAB complex uses the proton motif force (PMF) to energize the bacterial flagellum, it remains to be shown how the use of the PMF by SiiAB assists T1SS function and ultimately Salmonella invasion.