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Borzutzky, Arturo

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Borzutzky

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Arturo

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Borzutzky, Arturo

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2012 - 20142

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Author's Publications: search.filters.isAuthorOfPublication.891f11ab-c78e-462a-a1e0-d0bf67606046

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    Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function
    (The Rockefeller University Press, 2014) Kumar, Lalit; Chou, Janet; Yee, Christina; Borzutzky, Arturo; Vollmann, Elisabeth H.; von Andrian-Werburg, Ulrich; Park, Shin-Young; Hollander, Georg; Manis, John; Poliani, P. Luigi; Geha, Raif
    Lrrc8a is a ubiquitously expressed gene that encodes a leucine-rich repeat (LRR)–containing protein detected at higher levels on the surface of thymocytes than on other immune cells. We generated Lrrc8a−/− mice to investigate the role of LRRC8A in lymphocyte development and function. Lrrc8a−/− mice had increased prenatal and postnatal mortality, growth retardation, and multiple tissue abnormalities. Lrrc8a−/− mice displayed a modest block in B cell development but intact intrinsic B cell function. In contrast, both Lrrc8a−/− mice and Lrrc8a−/−→Rag2−/− bone marrow chimeras exhibited a severe cell-intrinsic block in early thymic development, with decreased proliferation and increased apoptosis of thymocytes, and impaired peripheral T cell function. Thymic epithelial cells expressed an LRRC8A ligand that was critical for double-negative to double-positive thymocyte differentiation and survival in vitro. LRRC8A constitutively associated with the GRB2–GAB2 complex and lymphocyte-specific protein tyrosine kinase (LCK) in thymocytes. LRRC8A ligation activated AKT via the LCK–ZAP–70–GAB2–PI3K pathway, and AKT phosphorylation was markedly reduced in the thymus of Lrrc8a−/− mice. These findings reveal an essential role for LRRC8A in T cell development, survival, and function.
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    DOCK8 Functions as an Adaptor that Links TLR–MyD88 Signaling to B Cell Activation
    (Nature Publishing Group, 2012) Rauter, Ingrid; Recher, Mike; Wakim, Rima; Dbaibo, Ghassan; Dasouki, Majed; Barlan, Isil; Baris, Safa; Kutukculer, Necil; Ochs, Hans; Plebani, Alessandro; Kanariou, Maria; Lefranc, Gerard; Reisli, Ismail; Fitzgerald, Katerine; Golenbock, Douglas; Keles, Sevgi; Ceja, Reuben; Jabara, Haifa Halim; McDonald, Douglas; Janssen, Erin; Massaad, Michel; Ramesh, Narayanaswamy; Borzutzky, Arturo; Benson, Halli Louise; Schneider, Lynda; Baxi, Sachin; Notarangelo, Luigi; Al-Herz, Waleed; Manis, John; Chatila, Talal; Geha, Raif
    DOCK8 and MyD88 have been implicated in serologic memory. Here we report antibody responses were impaired and \(CD27^+\) memory B cells were severely reduced in DOCK8-deficient patients. Toll-like receptor 9 (TLR9)- but not CD40-driven B cell proliferation and immunoglobulin production were severely reduced in DOCK8-deficient B cells. In contrast, TLR9-driven expression of AICDA, CD23 and CD86, and activation of NF-κB, p38 and Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. Following TLR9 ligation, DOCK8 became tyrosine phosphorylated by Pyk2, bound the Src family kinase Lyn and linked TLR9 to a Src-Syk-STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.