The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane

Edo D. Elstak, Maaike Neeft, Nadine T. Nehme, Jarno Voortman, Marc Cheung, Monireh Goodarzifard, Hans C. Gerritsen, Paul M.P. van Bergen en Henegouwen, Isabelle Callebaut, Geneviève de Saint Basile, Peter D. van der Sluijs: The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane. In: Blood, vol. 118, no. 6, pp. 1570-1578, 2011, (cited By (since 1996) 12).

Abstract

Cytotoxic T lymphocytes (CTLs) kill target cells through the polarized release of lytic molecules from secretory lysosomes. Loss of munc13-4 function inhibits this process and causes familial hemophagocytic lymphohistiocytosis type 3 (FHL3). munc13-4 binds rab27a, but the necessity of the complex remains enigmatic, because studies in knockout models suggest separate functions. In the present study, we describe a noncanonical rab27abinding motif in the N-terminus of munc13-4. Point mutants in this sequence have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. The munc13- 4 - rab27a complex is not needed for secretory lysosome maturation, as shown by complementation in CTLs from FHL3 patients and in a mast cell line silenced for munc13-4. In contrast, fusion of secretory lysosomes with, and content release at the plasma membrane during degranulation, strictly required the munc13-4 - rab27a complex. Total internal reflection fluorescence microscopy imaging revealed that the complex corrals motile secretory lysosomes beneath the plasma membrane during degranulation and controls their docking. The propensity to stall motility of secretory lysosomes is lost in cells expressing munc13-4 point mutants that do not bind rab27. In summary, these results uncovered a mechanism for tethering secretory lysosomes to the plasma membrane that is essential for degranulation in immune cells. © 2011 by The American Society of Hematology.

BibTeX (Download)

@article{Elstak20111570,
title = {The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane},
author = {Edo D. Elstak and Maaike Neeft and Nadine T. Nehme and Jarno Voortman and Marc Cheung and Monireh Goodarzifard and Hans C. Gerritsen and Paul M.P. van Bergen en Henegouwen and Isabelle Callebaut and Geneviève de Saint Basile and Peter D. van der Sluijs},
url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-80051639052&partnerID=40&md5=4369791a6d23655b138e96021245dbfc},
year  = {2011},
date = {2011-01-01},
journal = {Blood},
volume = {118},
number = {6},
pages = {1570-1578},
abstract = {Cytotoxic T lymphocytes (CTLs) kill target cells through the polarized release of lytic molecules from secretory lysosomes. Loss of munc13-4 function inhibits this process and causes familial hemophagocytic lymphohistiocytosis type 3 (FHL3). munc13-4 binds rab27a, but the necessity of the complex remains enigmatic, because studies in knockout models suggest separate functions. In the present study, we describe a noncanonical rab27abinding motif in the N-terminus of munc13-4. Point mutants in this sequence have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. The munc13- 4 - rab27a complex is not needed for secretory lysosome maturation, as shown by complementation in CTLs from FHL3 patients and in a mast cell line silenced for munc13-4. In contrast, fusion of secretory lysosomes with, and content release at the plasma membrane during degranulation, strictly required the munc13-4 - rab27a complex. Total internal reflection fluorescence microscopy imaging revealed that the complex corrals motile secretory lysosomes beneath the plasma membrane during degranulation and controls their docking. The propensity to stall motility of secretory lysosomes is lost in cells expressing munc13-4 point mutants that do not bind rab27. In summary, these results uncovered a mechanism for tethering secretory lysosomes to the plasma membrane that is essential for degranulation in immune cells. © 2011 by The American Society of Hematology.},
note = {cited By (since 1996) 12},
keywords = {},
pubstate = {published},
tppubtype = {article}
}