GRIPAP1 is an endosomal tethering factor mediating platelet α-granule biogenesis

Platelet α-granules are lysosome-related organelles produced in megakaryocytes, the platelet precursor cells. The biogenesis of α-granules is incompletely understood but depends on common endosomal pathways. Here, we discovered GRIPAP1, a partially characterized ubiquitous protein, as a new component of the α-granule biogenesis machinery. GRIPAP1-deficient megakaryocytes showed a significant decrease of α-granule numbers and overall cargo levels. In WT megakaryocytes, fibrinogen taken up by endocytosis and newly synthesized PF4 trafficked through GRIPAP1-labeled compartments en route to α-granules. GRIPAP1 localized to endosome subdomains decorated by Rab4a and Stx12, known players in α-granule biogenesis. GRIPAP1 bound GTP-loaded Rab4a, a key interaction for GRIPAP1 recruitment to membranes. Biochemically, GRIPAP1 behaved as an elongated homodimer akin to membrane tethering factors. Consistently, artificial mislocalization of GRIPAP1 to the mitochondria was sufficient to recruit Rab4a compartments containing internalized transferrin and newly synthesized PF4 to mitochondria. Together, the data advance understanding of endosomal transport, the biogenesis of α-granules, and likely other endo-lysosomal organelles.