TRAPPC1 is essential for the maintenance and differentiation of common myeloid progenitors in mice

Myeloid cell development in bone marrow is essential for the maintenance of peripheral immune homeostasis. However, the role of intracellular protein trafficking pathways during myeloid cell differentiation is currently unknown. By mining bioinformatics data, we identify trafficking protein particle complex subunit 1 (TRAPPC1) as continuously upregulated during myeloid cell development. Using inducible ER‐TRAPPC1 knockout mice and bone marrow chimeric mouse models, we demonstrate that TRAPPC1 deficiency causes severe monocyte and neutrophil defects, accompanied by a selective decrease in common myeloid progenitors (CMPs) and subsequent cell subsets in bone marrow. TRAPPC1‐deleted CMPs differentiate poorly into monocytes and neutrophils in vivo and in vitro , in addition to exhibiting enhanced endoplasmic reticulum stress and apoptosis via a Ca 2+ ‐mitochondria‐dependent pathway. Cell cycle arrest and senescence of TRAPPC1‐deleted CMPs are mediated by the activation of pancreatic endoplasmic reticulum kinase and the upregulation of cyclin‐dependent kinase inhibitor p21. This study reveals the essential role of TRAPPC1 in the maintenance and differentiation of CMPs and highlights the significance of protein processing and trafficking processes in myeloid cell development. Synopsis TRAPPC1 controls mouse myeloid cell development in the bone marrow by maintaining the homeostasis of the endoplasmic reticulum and the Golgi apparatus in common myeloid progenitors. TRAPPC1 is upregulated during myeloid cell development and controls differentiation of common myeloid progenitors (CMPs). TRAPPC1 deficiency causes ER and Golgi abnormalities and enhances endoplasmic reticulum stress in CMPs. TRAPPC1 deletion leads to apoptosis of CMPs via an ER stress‐Ca 2+ −mitochondria‐dependent pathway. TRAPPC1 deletion causes cell cycle arrest and senescence of CMPs via the PERK‐p21 signaling pathway. Graphical Abstract TRAPPC1 controls mouse myeloid cell development in the bone marrow by maintaining the homeostasis of the endoplasmic reticulum and the Golgi apparatus in common myeloid progenitors.