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

Abstract

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 Ca2+‐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.

Trappc1 intrinsically prevents ferroptosis of naive T cells to avoid spontaneous autoinflammatory disease in mice

“…In the meantime, TRAP-PIII was known to play an important role in autophagy and was found in the preautophagosomal structure [50]. TRAPP is composed of 10 subunits, and Trappc1 is one of the main members of the TRAPP family [28,51]. In our study, we found that Trappc1 deficiency in naive T cells significantly increased the ER to Golgi transport defect and UPR pathway with upregulated intracellular Ca 2+ level, and ER stress-related genes such as Atf4 and Chop.…”

“…We purchased CD45.1 + C57BL/6J (B6) background mice from Beijing University Experimental Animal Center. Trappc1 loxp/loxp mice and ER‐Cre mice were kindly provided by Dr. Lianfeng Zhang of the Institute of Laboratory Animal Science [28]. We also obtained CD4‐cre mice from Dr. Baojun Zhang of Xi'an Jiaotong University.…”

“…Also, recent studies have extended Rab1a's function to regulate more signaling pathways such as mTOR and notch [26,27]. Recently, we demonstrated that Trappc1 deficiency specifically in thymic epithelial cells and myeloid cells, respectively, caused remarkable developing defects of these cell lineages in mice [21,28]. However, the significance of the intrinsically expressing Trappc1 in T cells remains unknown.…”

mTORC2 orchestrates monocytic and granulocytic lineage commitment by an ATF5-mediated pathway

“…MEPs (Lin − Sca1 − c-Kit + CD34 − CD16/32 - ), CMPs (Lin − Sca1 − c-Kit + CD34 hi CD16/32 - ), and GMPs (Lin − Sca1 − c-Kit + CD34 hi CD16/32 hi ) were detected by flow cytometry with a gating strategy ( Figure S6 B). 32 , 33 Our results showed that the percentages and cell numbers of CMPs and GMPs were significantly lower in the bone marrow of tamoxifen-treated ER-Rictor KO mice compared to tamoxifen-treated WT mice, while no significant changes in MEPs were detected in tamoxifen-treated ER-Rictor KO mice ( Figures 2 A–2C). MDPs are generally thought to yield monocyte-committed progenitors, known as cMoPs, which further develop into mature monocytes.…”