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TAPBPR promotes editing of the HLA-B*44 peptide repertoire, increasing the presentation of peptides containing a C-terminal tryptophan

ABSTRACT: Major histocompatibility complex class I (MHC-I) molecules play a key part in the adaptive immune response through the presentation of antigens to CD8+ T cells. The high degree of polymorphism in MHC-I leads to significant variation in their dependence on components of the antigen processing and presentation pathway such as TAP and tapasin, and their affinity for the peptide editor TAPBPR. Here, we investigated the influence of TAPBPR on the cell surface phenotype and peptide repertoire presented by two human leukocyte antigen (HLA) class I allotypes, HLA-B*44:02 and -B*44:05, which are known to differ drastically in their dependence on tapasin. While TAPBPR exhibits a reduced ability to bind to HLA-B molecules compared to HLA-A, we found that it could bind to both HLA-B*44:02 and -B*44:05. In contrast to tapasin depletion, loss of TAPBPR has a limited effect on cell surface expression of these two molecules. Analysis of the immunopeptidomes presented in the presence and absence of TAPBPR revealed while TAPBPR expression restricted the peptide repertoire presented on HLA-B*44:05, it diversified the repertoire presented on HLA-B*44:02. Overall, TAPBPR improved the predicted affinity of the peptides displayed on both the HLA-B*44 molecules. Furthermore, TAPBPR enhanced the presentation of peptides containing a C-terminal tryptophan residue. Our results show that TAPBPR can significantly impact the peptide repertoire of MHC-I molecules to which it binds weakly. Furthermore, this represents the first study which points to a role for TAPBPR in the selection of a specific peptide sequence on MHC class I molecules.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cervix Carcinoma

SUBMITTER: Marcel Wacker

LAB HEAD: Juliane Walz

PROVIDER: PXD063219 | Pride | 2025-10-24

REPOSITORIES: Pride

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			Action	DRS
	220530_MW_HeLa_B4402_KD_W6-32_17_share_400-650mz_5Reps_Coprocessed.msf	Msf
	220530_MW_HeLa_B4402_KD_W6-32_17_share_DDA1_400-650mz_msms35.msf	Msf
	220530_MW_HeLa_B4402_KD_W6-32_17_share_DDA1_400-650mz_msms35.raw	Raw
	220530_MW_HeLa_B4402_KD_W6-32_17_share_DDA2_400-650mz_msms36.msf	Msf
	220530_MW_HeLa_B4402_KD_W6-32_17_share_DDA2_400-650mz_msms36.raw	Raw

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Project description:Background Dysregulation of major histocompatibility complex (MHC) class I antigen processing and presentation machinery (APM) components in the tumor as one main molecular mechanism of immune escape leading to deactivation of T cell immune surveillance could be due to post-transcriptional regulation via immune-modulatory microRNAs (miRNA). It is now well established from a variety of studies that several miRNAs could effectively modulate the expression of some MHC class I APM components in tumors. Tapasin is an important APM molecule involved in the association of MHC class I with transporter associated with antigen processing (TAP) and peptide loading. Since so far no detailed investigation of the posttranscriptional regulation of tapasin exists, the aim of this study is to identify and functionally characterize miRNAs targeting tapasin in melanoma. Methods Using miRNA trapping by RNA in vitro affinity purification (miTRAP) and in silico as well as small RNA sequencing, miRNAs will be identified, which bind to the 3'untranslated region (3' UTR) of tapasin. Dual luciferase assays will be performed to determine binding of the miRNA. In silico analysis was performed to predict the effect of miRNAs on the survival of melanoma patients in correlation to tapasin. RT-qPCR, Western blot, flow cytometry and other functional assays were performed after transfecting miRNA mimics in three melanoma cell lines. Results Using the combination strategy of miTRAP and RNA seq we identified miR-155-5p to bind to the 3’UTR of tapasin, which was further confirmed by in silico analysis and dual luciferase reporter assay. Transfection of miR-155-5p mimics demonstrated that miR-155-5p upregulate tapasin protein level, which was accompanied by an upregulation of the MHC class I (HLA-ABC) surface expression. Simultaneously, in several different types of cancer, including melanoma, the expression of miR-155-5p is significantly positively correlated with the patient's survival and HLA-A protein. Conclusion Our data revealed for the first time a positive role of miR-155-5p in the posttranscriptional regulation of tapasin in melanoma and provide further insights into the miR-155-5p-mediated induction of HLA-ABC surface expression. This might lead to a better T cell response, avoidance tumor cell escape, improvement of patients' survival and thus might be a potential therapeutic target.

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TAPBPR promotes editing of the HLA-B*44 peptide repertoire, increasing the presentation of peptides containing a C-terminal tryptophan

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