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PIP2-dependent regulation of Munc13-4 endocytic recycling: impact on the cytolytic secretory pathway.

Abstract：

:Cytotoxic lymphocytes clear infected and transformed cells by releasing the content of lytic granules at cytolytic synapses, and the ability of cytolytic effectors to kill in an iterative manner has been documented previously. Although bidirectional trafficking of cytolytic machinery components along the endosomal pathway has begun to be elucidated, the molecular mechanisms coordinating granule retrieval remain completely unexplored. In the present study, we focus on the lytic granule priming factor Munc13-4, the mutation of which in familial hemophagocytic lymphohistiocytosis type 3 results in a profound defect of cytotoxic function. We addressed the role of phosphatidylinositol (4,5)-bisphosphate (PIP2) in the regulation of Munc13-4 compartmentalization. We observed that in human natural killer cells, PIP2 is highly enriched in membrane rafts. Granule secretion triggering induces a transient Munc13-4 raft recruitment, followed by AP-2/clathrin-dependent internalization. Phosphatidylinositol 4-phosphate 5-kinase (PIP5K) γ gene silencing leads to the impairment of granule secretion associated with increased levels of raft-associated Munc13-4, which is attributable to a defect in AP-2 membrane recruitment. In such conditions, the ability to subsequently kill multiple targets was significantly impaired. These observations indicate that Munc13-4 reinternalization is required for the maintenance of an intracellular pool that is functional to guarantee the serial killing potential.

journal_name

Blood

journal_title

Blood

authors

Capuano C,Paolini R,Molfetta R,Frati L,Santoni A,Galandrini R

doi

10.1182/blood-2010-12-324160

subject

Has Abstract

pub_date

2012-03-08 00:00:00

pages

2252-62

issue

10

eissn

0006-4971

issn

1528-0020

pii

blood-2010-12-324160

journal_volume

119

pub_type

杂志文章

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