Mast cell regranulation requires a metabolic switch involving mTORC1 and a glucose-6-phosphate transporter
Jason A. Iskarpatyoti, Jianling Shi, Mathew Abraham, Abhay P. S. Rathore, Yuxuan Miao, Soman N. Abraham
Abstract
Mast cells (MCs) are granulated cells implicated in inflammatory disorders because of their capacity to degranulate, releasing prestored proinflammatory mediators. As MCs have the unique capacity to reform granules following degranulation in vitro, their potential to regranulate in vivo is linked to their pathogenesis. It is not known what factors regulate regranulation, let alone if regranulation occurs in vivo. We report that mice can undergo multiple bouts of MC regranulation following successive anaphylactic reactions. mTORC1, a nutrient sensor that activates protein and lipid synthesis, is necessary for regranulation. mTORC1 activity is regulated by a glucose-6-phosphate transporter, Slc37a2, which increases intracellular glucose-6-phosphate and ATP during regranulation, two upstream signals of mTOR. Additionally, Slc37a2 concentrates extracellular metabolites within endosomes, which are trafficked into nascent granules. Thus, the metabolic switch associated with MC regranulation is mediated by the interactions of a cellular metabolic sensor and a transporter of extracellular metabolites into MC granules.