What is the role of alternate splicing in antigen presentation by major histocompatibility complex class I molecules?

Belicha-Villanueva, Alan; Blickwedehl, Jennifer; McEvoy, Sarah; Golding, Michelle; Gollnick, Sandra O.; Bangia, Naveen

doi:10.1007/s12026-009-8123-8

Cited by 24 publications

(21 citation statements)

References 120 publications

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“…Recent findings suggest that tapasin may undergo alternative splicing (reviewed in Belicha-Villanueva et al, 2010a). For instance, a mutation found within a tapasin sequence derived from a cDNA database has been found to result in alternative splicing, which generates a soluble form of tapasin (Gao et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Productive association between MHC class I and tapasin requires the tapasin transmembrane/cytosolic region and the tapasin C-terminal Ig-like domain

Simone

Georgesen

Simone

et al. 2012

Molecular Immunology

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The current model of antigen assembly with major histocompatibility complex (MHC) class I molecules posits that interactions between the tapasin N-terminal immunoglobulin (Ig)-like domain and the MHC class I peptide-binding groove permit tapasin to regulate antigen selection. Much less is known regarding interactions that might involve the tapasin C-terminal Ig-like domain. Additionally, the tapasin transmembrane/cytoplasmic region enables tapasin to bridge the MHC class I molecule to the transporter associated with antigen processing (TAP). In this investigation, we made use of two tapasin mutants to determine the relative contribution of the tapasin C-terminal Ig-like domain and the tapasin transmembrane/cytoplasmic region to the assembly of MHC class I molecules. Deletion of a loop within the tapasin C-terminal Ig-like domain (Δ334-342) prevented tapasin association with the MHC class I molecule Kd. Although tapasin Δ334-342 did not increase the efficiency of Kd folding, Kd surface expression was enhanced on cells expressing this mutant relative to tapasin-deficient cells. In contrast to tapasin Δ334-342, a soluble tapasin mutant lacking the transmembrane/cytoplasmic region retained the ability to bind to Kd molecules, but did not facilitate Kd surface expression. Furthermore, when soluble tapasin and tapasin Δ334-342 were co-expressed, soluble tapasin had a dominant negative effect on the folding and surface expression of not only Kd, but also Db and Kb. In addition, our molecular modeling of the MHC class I-tapasin interface revealed novel potential interactions involving tapasin residues 334-342. Together, these findings demonstrate that the tapasin C-terminal and transmembrane/cytoplasmic regions are critical to tapasin's capacity to associate effectively with the MHC class I molecule.

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Section: Discussionmentioning

confidence: 99%

Productive association between MHC class I and tapasin requires the tapasin transmembrane/cytosolic region and the tapasin C-terminal Ig-like domain

Simone

Georgesen

Simone

et al. 2012

Molecular Immunology

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“…The functional immune system uses pre-mRNA splicing to expand its gene function to adapt to rapidly changing environmental conditions in a precise way (37). Many immunologically relevant genes have been found to undergo alternative splicing, thus revealing another new layer of complexity in immune gene regulation (38).…”

Section: Discussionmentioning

confidence: 99%

The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A

Dai

Zhang

et al. 2012

The Journal of Immunology

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The MHC class I (MHC I) molecules play a pivotal role in the regulation of immune responses by presenting antigenic peptides to CTLs and by regulating cytolytic activities of NK cells. In this article, we show that MHC I A in rhesus macaques can be alternatively spliced, generating a novel MHC I A isoform (termed “MHC I A-sv1”) devoid of α3 domain. Despite the absence of β2-microglobulin (β2m), the MHC I A-sv1 proteins reached the cell surface of K562-transfected cells as endoglycosidase H-sensitive glycoproteins that could form disulfide-bonded homodimers. Cycloheximide-based protein chase experiments showed that the MHC I A-sv1 proteins were more stable than the full-length MHC I A in transiently or stably transfected cell lines. Of particular interest, our studies demonstrated that MHC I A-sv1 could form β2m-free heterodimers with its full-length protein in mammalian cells. The formation of heterodimers was accompanied by a reduction in full-length MHC I A ubiquitination and consequent stabilization of the protein. Taken together, these results demonstrated that MHC I A-sv1 and MHC I A can form a novel heterodimeric complex as a result of the displacement of β2m and illustrated the relevance of regulated MHC I A protein degradation in the β2m-free heterodimerization-dependent control, which may have some implications for the MHC I A splice variant in the fine tuning of classical MHC I A/TCR and MHC I A/killer cell Ig-like receptor interactions.

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“…It thus seems unlikely that these splice variants directly participate in the antigen presentation. Alternative splicing of mRNA transcripts is increasingly regarded as an extra mechanism to increase MHC diversity (Belicha-Villanueva et al, 2010). Up to 70% of MHC transcripts have been reported to undergo alternative splicing in different species.…”

Section: Alternatively Splice Isoforms Of Anda-mhc Genesmentioning

confidence: 99%

Extensive diversification of MHC in Chinese giant salamanders Andrias davidianus (Anda-MHC) reveals novel splice variants

Zhu

Chen

Wang

et al. 2014

Developmental & Comparative Immunology

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What is the role of alternate splicing in antigen presentation by major histocompatibility complex class I molecules?

Cited by 24 publications

References 120 publications

Productive association between MHC class I and tapasin requires the tapasin transmembrane/cytosolic region and the tapasin C-terminal Ig-like domain

Productive association between MHC class I and tapasin requires the tapasin transmembrane/cytosolic region and the tapasin C-terminal Ig-like domain

The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A

Extensive diversification of MHC in Chinese giant salamanders Andrias davidianus (Anda-MHC) reveals novel splice variants

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