A novel Munc13-4/S100A10/annexin A2 complex promotes Weibel–Palade body exocytosis in endothelial cells

Abstract

The tethering factor Munc13-4 is recruited to Weibel–Palade body (WPB) fusion sites after secretagogue stimulation to promote WPB exocytosis. Annexin A2-S100A10 is a novel Munc13-4 interaction partner assisting Munc13-4 tethering at the plasma membrane.

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

“…In our work, partly confirmed by others on other family members, we find that the first two members of the annexin protein family of calcium-binding proteins are dysfunctional in CF 21,22,101 alongside our reported NDPK defects. Combining our data with the known functions of annexin A2 in membrane hub assembly and signaling of exocytosis as proposed by the Gerke group, 92 for example, our model predicts platelet dysfunction in CF. The authors were unaware of certain platelet CF literature at the time of using the model of 'annexin-NDPK-opathy' as a prediction tool.…”

“…Interestingly, a novel Munc13-4/S100A10/ Annexin A2 complex has been shown to support acute Weibel-Palade body (WPBs) exocytosis by tethering WPBs to the plasma membrane via Annexin A2-S100A10 in endothelial cells. 92 Thus a wealth of disparate data from embryogenesis where cell tip migration, cell corpse disposal, autophagy, and endosome fusion events have been recently linked to new membrane synthesis through fat metabolism are beginning to point to aspects of CF disease that are otherwise difficult to explain. A key hurdle is that those who research CFTR as a cause of CF do not share a research agenda with developmental biologists interested in tracheal formation, and in particular it is becoming clear that the embryo can reuse exocytotic events needed for mucus release during fetal lumen formation.…”

Exocytosis of Weibel–Palade bodies: how to unpack a vascular emergency kit

“…Activated RalA most likely coordinates a tethering step by promoting Arf6‐dependent phospholipase D1 (PLD1) activity . Local modification of phospholipids by PLD1 generates plasma membrane microdomains that recruit the Ca 2+ ‐binding and phospholipid‐binding AnxA2–S100A10 complex, which, in its turn, links WPBs to membrane fusion sites through the WPB‐localized tethering factor Munc13‐4 . Ca 2+ ‐mediated VWF secretion is also dependent on rapid changes in the actin cytoskeleton that lead to the formation of parallel stress fibers, a process that is primarily regulated by GTPases of the Rho family .…”

“…On the other hand, actin acts as a barrier , and, by anchoring WPBs to the actin cytoskeleton, MyRIP acts as a brake during exocytosis . Munc13‐4 binds both Rab27A and Rab15, and promotes exocytosis by tethering WPBs to release sites on the plasma membrane, which contain the annexin A2–S100A10 complex . Slp4‐a interacts with Rab3 isoforms and Rab27A, in an activity‐insensitive manner with the latter, and promotes WPB exocytosis by providing the link between the WPB and members of the SNARE complex .…”

Weibel−Palade bodies at a glance

“…Interestingly, some overlapping binding partners have been identified, potentially offering clues as to the function of these Rab proteins. For example, both Rab27a and Rab15 bind Munc 13-4 (also known as UNC13D) (Zografou et al, 2012), which is required for agonist-stimulated release of VWF (Chehab et al, 2017;Zografou et al, 2012). Furthermore, Rab27a and Rab3 (isoforms B and D) also share a binding partner in synaptotagminlike protein 4 (Slp4-a; also known as SYTL4) (Bierings et al, 2012).…”