TY - JOUR
T1 - Formins Regulate the Actin-Related Protein 2/3 Complex-Independent Polarization of the Centrosome to the Immunological Synapse
AU - Gomez, Timothy S.
AU - Kumar, Karan
AU - Medeiros, Ricardo B.
AU - Shimizu, Yoji
AU - Leibson, Paul J.
AU - Billadeau, Daniel D D.
N1 - Funding Information:
We would like to thank R.A. Schoon and C.J. Dick for their help with the cytotoxicity assays. This work was supported by the Mayo Foundation, NIH grant R01-AI065474 to D.D.B., NIH grant F31-AI068624 to T.S.G., NIH grant R01-CA47752 to P.J.L., and NIH grants R01-AI038474 and R01-AI031126 to Y.S. The authors declare that they have no competing financial interests.
PY - 2007/2/23
Y1 - 2007/2/23
N2 - T cell receptor (TCR)-mediated cytoskeletal reorganization is considered to be actin-related protein (Arp) 2/3 complex dependent. We therefore examined the requirement for Arp2/3- and formin-dependent F-actin nucleation during T cell activation. We demonstrated that without Arp2/3-mediated actin nucleation, stimulated T cells could not form an F-actin-rich lamellipod, but instead produced polarized filopodia-like structures. Moreover, the microtubule-organizing center (MTOC, or centrosome), which rapidly reorients to the immunological synapse through an unknown mechanism, polarized in the absence of Arp2/3. Conversely, the actin-nucleating formins, Diaphanous-1 (DIA1) and Formin-like-1 (FMNL1), did not affect TCR-stimulated F-actin-rich structures, but instead displayed unique patterns of centrosome colocalization and controlled TCR-mediated centrosome polarization. Depletion of FMNL1 or DIA1 in cytotoxic lymphocytes abrogated cell-mediated killing. Altogether, our results have identifed Arp2/3 complex-independent cytoskeletal reorganization events in T lymphocytes and indicate that formins are essential cytoskeletal regulators of centrosome polarity in T cells.
AB - T cell receptor (TCR)-mediated cytoskeletal reorganization is considered to be actin-related protein (Arp) 2/3 complex dependent. We therefore examined the requirement for Arp2/3- and formin-dependent F-actin nucleation during T cell activation. We demonstrated that without Arp2/3-mediated actin nucleation, stimulated T cells could not form an F-actin-rich lamellipod, but instead produced polarized filopodia-like structures. Moreover, the microtubule-organizing center (MTOC, or centrosome), which rapidly reorients to the immunological synapse through an unknown mechanism, polarized in the absence of Arp2/3. Conversely, the actin-nucleating formins, Diaphanous-1 (DIA1) and Formin-like-1 (FMNL1), did not affect TCR-stimulated F-actin-rich structures, but instead displayed unique patterns of centrosome colocalization and controlled TCR-mediated centrosome polarization. Depletion of FMNL1 or DIA1 in cytotoxic lymphocytes abrogated cell-mediated killing. Altogether, our results have identifed Arp2/3 complex-independent cytoskeletal reorganization events in T lymphocytes and indicate that formins are essential cytoskeletal regulators of centrosome polarity in T cells.
KW - CELLBIO
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=33847311403&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847311403&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2007.01.008
DO - 10.1016/j.immuni.2007.01.008
M3 - Article
C2 - 17306570
AN - SCOPUS:33847311403
SN - 1074-7613
VL - 26
SP - 177
EP - 190
JO - Immunity
JF - Immunity
IS - 2
ER -