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TACI Isoforms Regulate Ligand Binding and Receptor Function.

ABSTRACT: TACI signals activate B cell proliferation, isotype switch and antibody production in both normal immunity and autoimmune states. In contrast to murine TACI, the human TACI gene undergoes alternative splicing to produce short and long isoforms (TACI-S and TACI-L). In previous studies, we showed that transduction of the short, but not long isoform, into murine B cells or human pre-B cells lacking TACI, caused them to become transcriptional and morphologically identical to plasma cells. These data suggest that the expression of different isoforms in humans provides unique controls on B cell maturation. In these studies we show that TACI-S and TACI-L form complexes in a ligand-independent manner, not dependent on a single extracellular domain. Both TACI isoforms are detectable in the endosomal cellular compartment where they co-localize with MyD88, TRAF6, and the activated 65 kDa form of TLR9, depending on a conserved intracellular TACI sequence. In contrast to TACI-L expressing cells, or cells bearing both isoforms, TACI-S binds ligands BAFF and APRIL with substantially greater affinity and promotes enhanced NF-kB activation. Using isoform-specific monoclonal antibodies, we show that while TACI-L is predominant as a surface receptor surface on human B cells, significantly more TACI-S is noted in the intracellular compartment and also in marginal zone, isotype switched and plasmablast in resting B cells. TACI-S is increased in tonsillar B cells and also in the intracellular compartment of activated peripheral B cells. These data shows that alternative splicing of the human TACI gene leads to two isoforms both of which intersect with MyD88 and TRAF6 and form complexes with TLR9, but the two isoforms have different ligand binding capacities, subcellular locations and activation capabilities.

SUBMITTER: Garcia-Carmona Y

PROVIDER: S-EPMC6176016 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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TACI Isoforms Regulate Ligand Binding and Receptor Function.

Garcia-Carmona Yolanda Y Ting Adrian T AT Radigan Lin L Athuluri Divakar Sai Krishna SK Chavez Jose J Meffre Eric E Cerutti Andrea A Cunningham-Rundles Charlotte C

Frontiers in immunology 20181002

TACI signals activate B cell proliferation, isotype switch and antibody production in both normal immunity and autoimmune states. In contrast to murine TACI, the human TACI gene undergoes alternative splicing to produce short and long isoforms (TACI-S and TACI-L). In previous studies, we showed that transduction of the short, but not long isoform, into murine B cells or human pre-B cells lacking TACI, caused them to become transcriptional and morphologically identical to plasma cells. These data ...[more]

PMID: 30333819

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Project description:The D(2) dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D(4) subtype of dopamine receptor were tested on wild-type and mutant D(2) receptors. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D(2) receptor affinity when three non-conserved amino acids in TM2 and TM3 were mutated to the corresponding D(4) amino acids. The two ligands with the greatest improvement in affinity for the D(2) mutant receptor [i.e., 3-{[4-(4-iodophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine (L-750,667) and 1-[4-iodobenzyl]-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine (RBI-257)] were investigated in functional assays. Consistent with their higher affinity for the mutant than for the wild-type receptor, concentrations of L-750,667 or RBI-257 that produced large reductions in the potency of quinpirole's functional response in the mutant did not significantly reduce quinpirole's functional response in the wild-type D(2) receptor. In contrast to RBI-257 which is an antagonist at all receptors, L-750,667 is a partial agonist at the wild-type D(2) but an antagonist at both the mutant D(2) and wild-type D(4) receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D(2) dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non-conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermolecular steric contacts between the ligands and receptors. Consistent with the experimental data, this model illustrates the interactions between a variety of subtype-selective ligands and the wild-type D(2), mutant D(2), or wild-type D(4) receptors.

Dataset Information

TACI Isoforms Regulate Ligand Binding and Receptor Function.

Publications

TACI Isoforms Regulate Ligand Binding and Receptor Function.

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