Abstract
α1,6-Fucosyltransferase (Fut8) knock-out (Fut8(-/-)) mice showed an abnormality in pre-B cell generation. Membrane assembly of pre-BCR is a crucial checkpoint for pre-B cell differentiation and proliferation in both humans and mice. The assembly of pre-BCR on the cell surface was substantially blocked in the Fut8-knockdown pre-B cell line, 70Z/3-KD cells, and then completely restored by re-introduction of the Fut8 gene to 70Z/3-KD (70Z/3-KD-re) cells. Moreover, loss of α1,6-fucosylation (also called core fucosylation) of μHC was associated with the suppression of the interaction between μHC and λ5. In contrast to Fut8(+/+) CD19(+)CD43(-) cells, the subpopulation expressing the μHC·λ5 complex in the Fut8(-/-) CD19(+)CD43(-) cell fraction was decreased. The pre-BCR-mediated tyrosine phosphorylation of CD79a and activation of Btk were attenuated in Fut8-KD cells, and restored in 70Z/3-KD-re cells. The frequency of CD19(low)CD43(-) cells (pre-B cell enriched fraction) was also reduced in Fut8(-/-) bone marrow cells, and then the levels of IgM, IgG, and IgA of 12-week-old Fut8(-/-) mice sera were significantly lower than those of Fut8(+/+) mice. Our results suggest that the core fucosylation of μHC mediates the assembly of pre-BCR to regulate pre-BCR intracellular signaling and pre-B cell proliferation.
Highlights
Formation of a functional precursor B cell receptor is dependent on N-glycosylation of -heavy chains (HC)
We further explored a new mechanism of B lymphopoietic failure at the pre-B cell stage in Fut8Ϫ/Ϫ mice, and found that core fucosylation of HC was required for the assembly of precursor B cell receptor (pre-B cell receptor (BCR)) and intracellular signaling via pre-BCR
bone marrow (BM), as confirmed by fucose lectin, Aspergillus oryzae lectin (AOL) [16], a decrease of peripheral white blood cells in Fut8Ϫ/Ϫ mice suggest that Fut8 plays some positive roles in the regulation of hematopoiesis in the BM
Summary
Formation of a functional precursor B cell receptor (pre-BCR) is dependent on N-glycosylation of -heavy chains (HC). Our results suggest that the core fucosylation of HC mediates the assembly of pre-BCR to regulate pre-BCR intracellular signaling and pre-B cell proliferation. Functions of Fut in Early B Cell Development residue of hybrid and complex N-glycans via an ␣1,6-linkage (core fucosylation) in the Golgi apparatus in mammals [5] as shown in supplemental Fig. S1. It has been reported that Fut8Ϫ/Ϫ mice exhibited multiple behavioral abnormalities associated with a schizophrenia-like phenotype [10] Taken together, these results suggest that the core fucose plays a key role in regulating important physiological functions via the modification of functional proteins. We further explored a new mechanism of B lymphopoietic failure at the pre-B cell stage in Fut8Ϫ/Ϫ mice, and found that core fucosylation of HC was required for the assembly of pre-BCR and intracellular signaling via pre-BCR
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