TY - JOUR
T1 - Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells
AU - Boding, Lasse
AU - Hansen, Ann K
AU - Meroni, Germana
AU - Johansen, Bo B
AU - Braunstein, Thomas H
AU - Bonefeld, Charlotte M
AU - Kongsbak, Martin
AU - Jensen, Benjamin A H
AU - Woetmann, Anders
AU - Thomsen, Allan Randrup
AU - Odum, Niels
AU - von Essen, Marina R
AU - Geisler, Carsten
N1 - This article is protected by copyright. All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
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.
U2 - 10.1002/eji.201344388
DO - 10.1002/eji.201344388
M3 - Journal article
C2 - 25043946
SN - 0014-2980
VL - 44
SP - 3109
EP - 3118
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 10
ER -