Caspase-Independent Cell Death by CD300LF (MAIR-V), an Inhibitory Immunoglobulin-Like Receptor on Myeloid Cells

Abstract

The myeloid-associated Ig-like receptor family (CD300) consists of nine activating or inhibitory cell surface receptors preferentially expressed on myeloid cells and are encoded by the genes in a small cluster on mouse chromosome 11. One of the receptors, CD300LF (MAIR-V), has a long cytoplasmic tail containing two consensus ITIMs and an immunoreceptor tyrosine-based switching motif, suggesting that CD300LF regulates the activation of myeloid cells. However, the functional characteristics of this receptor are still incompletely understood. In this study, we demonstrate that cross-linking CD300LF with anti-CD300LF mAb induced cell death in peritoneal macrophages as well as in several transfectants expressing CD300LF. CD300LF-mediated cell death was dependent on the cytoplasmic region but did not require an ITIM or immunoreceptor tyrosine-based switching motif. Scanning electron microscopy revealed a loss of blebs from the surface of the dead cells mediated by CD300LF, a morphological feature similar to that observed in apoptotic cells. However, CD300LF-mediated cell death was not inhibited by a caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, or autophagy inhibitors, 3-methyladenine or N-acetyl-l-cystein. Moreover, the splicing isoform of a transcription factor, X-box binding protein-1, which is produced in dead cells as a response to endoplasmic reticulum stress, was not detected. Together, these results indicate that CD300LF mediates caspase and endoplasmic reticulum stress-independent cell death by a novel mechanism.

CD300F Blocks Both MyD88 and TRIF-Mediated TLR Signaling through Activation of Src Homology Region 2 Domain-Containing Phosphatase 1

“…Two putative ITIMs encompassing Y205 and Y249 have been identified, and a substitution (tyrosine into phenylalanine) analysis revealed that these were required for the CD300F-mediated inhibitory effects (8). However, the action mechanism of CD300F still requires more detailed analysis because cross-linking of mouse CD300F, in contrast to the previously mentioned results, augmented LPS response through its association with FcRg in mast cells (7) and induced apoptotic cell death in human acute myeloid leukemia and myeloid cells (9,10).…”

shRNA screening identifies JMJD1C as being required for leukemia maintenance

“…CD300LF was upregulated in mouse and human KD cells (supplemental Figures 4A and 5A,C) and in MLL-AF9 cells with Myb KD 41 and was shown to mediate cell death in myeloid cells. 58 Moreover, Cd300lf levels are partly restored with Myb or Myc overexpression in Jmjd1c-depleted cells, further implicating this gene in an Myb-Myc-Jmjd1c network ( Figure 7B). However, the CD300LF upregulation was apparent already before IPTG induction in SEM cells ( Figure 7C), which could be due to a potential leakiness of the inducible system and high sensitivity of CD300LF to JMJD1C depletion.…”

The CD300 molecules regulate monocyte and dendritic cell functions

“…Studies in mice indicate cross-linking CD300a and CD300f molecules can promote cell survival, possibly through activation of AKT (Izawa et al 2007). Human cell survival is inhibited by CD300a and CD300f, although they act as modifying agents, not direct inducers of apoptosis (Bachelet et al 2008(Bachelet et al , 2005Can et al 2008;Munitz et al 2006a).…”