TY - JOUR T1 - Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells. JF - Eur J Immunol Y1 - 2014 A1 - Boding, Lasse A1 - Hansen, Ann K A1 - Meroni, Germana A1 - Johansen, Bo B A1 - Braunstein, Thomas H A1 - Bonefeld, Charlotte M A1 - Kongsbak, Martin A1 - Jensen, Benjamin A H A1 - Woetmann, Anders A1 - Thomsen, Allan R A1 - Odum, Niels A1 - von Essen, Marina R A1 - Geisler, Carsten KW - Animals KW - Blotting, Western KW - Cytotoxicity, Immunologic KW - Exocytosis KW - Flow Cytometry KW - Mice KW - Mice, Knockout KW - Mice, Transgenic KW - Proteins KW - Reverse Transcriptase Polymerase Chain Reaction KW - Secretory Vesicles KW - T-Lymphocytes, Cytotoxic AB -

Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X-linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here, we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking, and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/-) CTLs completely rescued lytic granule exocytosis, and vice versa, knockdown of MID1 inhibited exocytosis of lytic granules in WT CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity.

VL - 44 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25043946?dopt=Abstract ER -