title: Sphingomyelinase D inhibits store-operated Ca2+ entry in T lymphocytes by suppressing ORAI current.
abstract: Infections caused by certain bacteria including Mycobacterium tuberculosis and Corynebacterium pseudotuberculosis provoke inflammatory responses characterized by the formation of granulomas with necrotic foci-so-called caseous necrosis. The granulomas of infected animals show prominent infiltration by T lymphocytes, and T cell depletion increases host mortality. Notorious zoonotic C. pseudotuberculosis secretes sphingomyelinase (SMase) D, a phospholipase that cleaves off the choline moiety of sphingomyelin, a phospholipid found primarily in the outer leaflet of host cell plasma membranes. Experimental C. pseudotuberculosis strains that lack SMase D are markedly less infectious and unable to spread in hosts, indicating that this enzyme is a crucial virulence factor for sustaining the caseous lymphadenitis infections caused by this microbe. However, the molecular mechanism by which SMase D helps bacteria evade the host's immune response remains unknown. Here, we find that SMase D inhibits store-operated Ca(2+) entry (SOCE) in human T cells and lowers the production of the SOCE-dependent cytokines interleukin-2, which is critical for T cell growth, proliferation, and differentiation, and tumor necrosis factor α, which is crucial for the formation and maintenance of granulomas in microbial infections. SMase D inhibits SOCE through a previously unknown mechanism, namely, suppression of Orai1 current, rather than through altering gating of voltage-gated K(+) channels. This finding suggests that, whereas certain genetic mutations abolish Orai1 activity causing severe combined immunodeficiency (SCID), bacteria have the ability to suppress Orai1 activity with SMase D to create an acquired, chronic SCID-like condition that allows persistent infection. Thus, in an example of how virulence factors can disrupt key membrane protein function by targeting phospholipids in host cell membranes, our study has uncovered a novel molecular mechanism that bacteria can use to thwart host immunity.
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: David J
authors.initials: DJ
authors.lastname: Combs
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 zhelu@mail.med.upenn.edu.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology*; D016466:CHO Cells; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D016925:Corynebacterium pseudotuberculosis / Q000201:enzymology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D000071740:ORAI1 Protein; D010727:Phosphoric Diester Hydrolases / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D015220:Calcium Channels; D007376:Interleukin-2; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D014409:Tumor Necrosis Factor-alpha; D010727:Phosphoric Diester Hydrolases; C055160:sphingomyelin phosphodiesterase D