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aid  cells  csr  dominant negative  dominant  effect  mast cells  mast  negative effect  negative  secretory granule  secretory  slc 
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Preview: International Immunology - Advance Access

International Immunology Advance Access





Published: Wed, 15 Nov 2017 00:00:00 GMT

Last Build Date: Wed, 15 Nov 2017 11:48:16 GMT

 



Lysosome biogenesis regulated by the amino-acid transporter SLC15A4 is critical for functional integrity of mast cells

2017-11-15

Abstract
Mast cells possess specialized lysosomes, so-called secretory granules, which play a key role not only in allergic responses but also in various immune disorders. The molecular mechanisms that control secretory-granule formation are not fully understood. Solute carrier family member 15A4 (SLC15A4) is a lysosome-resident amino-acid/oligopeptide transporter that is preferentially expressed in hematopoietic-lineage cells. Here we demonstrated that SLC15A4 is required for mast-cell secretory granule homeostasis, and limits mast-cell functions and inflammatory responses by controlling the mTORC1–TFEB signaling axis. In mouse Slc15a4−/− mast cells, diminished mTORC1 activity increased the expression and nuclear translocation of TFEB, which caused secretory granules to degranulate more potently. This alteration of TFEB function in mast cells strongly affected the FcεRI-mediated responses and IL-33–triggered inflammatory responses both in vitro and in vivo. Our results reveal a close relationship between SLC15A4 and secretory-granule biogenesis that is critical for the functional integrity of mast cells.



Depletion of recombination specific co-factors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination

2017-11-10

Abstract
Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with Hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild type WT AID whereas its mechanism remains unknown. We generated the JP41 (R190X) mutation in one allele and null mutation on the other allele in mouse B cell line (CH12F3-2A) using CRISPR/Cas9 genome editing tools and studied the effect of JP41 expression on the function of exogenously introduced WT AID fused with estrogen receptor (AIDER) in AID JP41/∆/AIDER CH12F3-2A cells. We found that JP41 expression strongly suppressed not only CSR but also Igh/c-Myc chromosomal translocations by AIDER. We showed the dominant negative effect is not evident at the DNA cleavage step but obvious at both deletional and inversional recombination steps. We also confirmed the dominant negative effect of other C-terminal mutants, JP8Bdel (R183X) and P20 (34-aa insertion at residue 182) in AID deficient spleen B cells. Finally, we showed that the expression of JP41 reduced the binding of AIDER with its cofactors (hnRNP L, SERBP1, and hnRNP U). Together these data indicate that dominant negative effect of JP41 on CSR is likely due to the depletion of the CSR-specific RNA binding proteins from WT AID.