Abstract
X-linked hyper-IgM (XHIM) syndrome is an immunological disorder resulting from mutations in the CD154 gene. Some mutations occur in splicing sites and result in transcripts encoding wild-type and mutant proteins. These mutants lack the tumor necrosis factor homologous (TNFH) domain and consequently fail to trimerize. Given that the TNFH domain is responsible for trimerization, one may predict that the TNFH mutant can not participate in the assembly of wild-type CD154. Thus, it was puzzling why these patients exhibit XHIM phenotype, presumably resulting from a lack of functional CD154. One possibility is that the TNFH mutant exhibits a dominant negative effect over the wild-type protein. To investigate this, we coexpressed the wild-type protein and a TNFH mutant and examined the biochemical and functional properties of the resulting CD154 products. We demonstrate that despite the lack of the TNFH domain, the TNFH mutant can associate with the wild-type protein. Furthermore, such an association compromises the ability of the wild-type protein to mature onto the cell surface. These results provide a mechanism for the defect of CD154 in XHIM patients producing both wild-type and TNFH variants and suggest that besides the TNFH domain, the stalk region participates in the assembly of CD154 trimers.
Highlights
X-linked hyper-IgM (XHIM) syndrome is an immunological disorder resulting from mutations in the CD154 gene
Such an association compromises the ability of the wild-type protein to mature onto the cell surface. These results provide a mechanism for the defect of CD154 in XHIM patients producing both wild-type and tumor necrosis factor homologous (TNFH) variants and suggest that besides the TNFH domain, the stalk region participates in the assembly of CD154 trimers
This observation is significant in at least two aspects. It indicates that whereas patient’s cells are capable of making both wild-type and TNFH(Ϫ) mutant CD154 protein, they may fail to produce sufficient functional CD154 on the surface of activated T cells, leading to the hyper-IgM phenotype. It suggests that, in addition to the TNFH domain, other region(s) of the CD154 structure may contribute to the assembly of CD154 trimers
Summary
Such an association compromises the ability of the wild-type protein to mature onto the cell surface These results provide a mechanism for the defect of CD154 in XHIM patients producing both wild-type and TNFH variants and suggest that besides the TNFH domain, the stalk region participates in the assembly of CD154 trimers. In some XHIM patients mutations in the donor splicing sites (see Ref. 13 and references therein) or the acceptor splicing sites [14] lead to generation of multiple species of mRNAs consisting of the wild-type and one or more aberrantly spliced transcripts within a single cell In each of these cases, the mis-spliced mRNA transcript encodes a variant of CD154 protein lacking either a major portion of, or the entire, TNFH domain [13, 14]. Our data revealed that the mutant protein still interacts with the wild-type protein despite the lack of the TNFH domain, defining a previously unrecognized structural element that contributes to CD154 trimer assembly
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