The life cycle of platelet granules

Abstract

Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules, α-granules, and lysosomes-although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways. Both are formed from the trans-Golgi network and early endosomes and mature in multivesicular bodies, but the formation of dense granules requires trafficking machinery different from that of α-granules. Following formation in the megakaryocyte body, both granule types are transported through and mature in long proplatelet extensions prior to the release of nascent platelets into the bloodstream. Granules remain stored in circulating platelets until platelet activation triggers the exocytosis of their contents. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, located on both the granules and target membranes, provide the mechanical energy that enables membrane fusion during both granulogenesis and exocytosis. The function of these core fusion engines is controlled by SNARE regulators, which direct the site, timing, and extent to which these SNAREs interact and consequently the resulting membrane fusion. In this review, we assess new developments in the study of platelet granules, from their generation to their exocytosis.

Keywords: Exocytosis; Granule; Platelet activation; Platelets.

Figure 1.. Working models of platelet α-granule and dense granule formation in megakaryocytes.

( A) α-Granules derive from two major pathways: synthetic and endocytic. The synthetic pathway originates at the trans-Golgi network (TGN). Soluble clathrin molecules recruited to the TGN self-assemble into a lattice structure and interact with coat proteins, presumed to be adaptor protein 1 (AP1), to form clathrin-coated pits. These pits invaginate to bud off early membrane-bound vesicles that are ultimately directed to early endosomes. Endocytic vesicles originate similarly at the plasma membrane employing adaptor protein 2 (AP2) and ultimately merge into early endosomes. α-Granules mature in multivesicular bodies (MVBs), a process that requires proteins VPS33B, VPS16B, and NBEAL2. ( B) Dense (δ) granules are lysosomal-related organelles, which are derived from the endosomal compartment. The current understanding of biogenesis of dense granule is highly speculative and was extrapolated from the biogenesis of melanosomes. Early endosomes provide input for developing dense granules, which may mature in MVBs. In melanosomes, BLOC1 is required for the exit of tubular structures carrying cargo from the endosomes, which are directed to the developing melanosomes by BLOC2. Alternatively, cargoes can be directed to developing dense granules by an AP3-dependent pathway, which may or may not require BLOC2. BLOC, biogenesis of lysosome-related organelles complex.

Figure 2.. SNARE-mediated platelet granule exocytosis.

The pathway of platelet granule exocytosis involves (1) granule docking, (2) priming, and (3) membrane fusion and cargo release. Rab27b and its effectors syntaptotagmin-like protein and Munc13-4 present on vesicle membrane are required for granule docking. Platelet activation promotes conformation change in syntaxins, sequestered by Munc18b in the resting state. This activation results in “priming” with subsequent formation of a four-helical bundle consisting of one R-SNARE provided by VAMP (red) and three Q-SNAREs provided by syntaxin and SNAP-23 (shades of green). In addition, syntaxin binding protein 5 (STXBP5) regulates t-SNARE function by binding syntaxin-SNAP-23 heterodimers. SNARE engagement ultimately leads to formation of the membrane fusion pore and cargo release. SNAP, soluble NSF attachment proteins; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; VAMP, vesicle-associated membrane protein.