Abstract
Peptide-dependent engagement between human leucocyte antigens class I (HLA-I) molecules and their cognate receptors has been extensively analyzed. HLA-F belongs to the non-classical HLA-Ib molecules with marginal polymorphic nature and tissue restricted distribution. The three common allelic variants HLA-F*01:01/01:03/01:04 are distinguished by polymorphism outside the peptide binding pockets (residue 50, α1 or residue 251, α3) and are therefore not considered relevant for attention. However, peptide selection and presentation undergoes a most elaborated extraction from the whole available proteome. It is known that HLA-F confers a beneficial effect on disease outcome during HIV-1 infections. The interaction with the NK cell receptor initiates an antiviral downstream immune response and lead to delayed disease progression. During the time of HIV infection, HLA-F expression is upregulated, while its interaction with KIR3DS1 is diminished. The non-polymorphic nature of HLA-F facilitates the conclusion that understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response. Utilizing soluble HLA technology we recovered stable pHLA-F*01:01, 01:03 and 01:04 complexes from K562 cells and analyzed the peptides presented. Utilizing a sophisticated LC-MS-method, we analyzed the complete K562 proteome and matched the peptides presented by the respective HLA-F subtypes with detected proteins. All peptides featured a length of 8 to 24 amino acids and are not N-terminally anchored; the C-terminus is preferably anchored by Lys. To comprehend the alteration of the pHLA-F surface we structurally compared HLA-F variants bound to selected peptides. The peptides were selected from the same cellular content; however, no overlap between the proteomic source of F*01:01, 01:03 or 01:04 selected peptides could be observed. Recognizing the balance between HLA-F expression, HLA-F polymorphism and peptide selection will support to understand the role of HLA-F in viral pathogenesis.
Highlights
HLA-F belongs to the family of HLA-Ib molecules and is of the whole HLA genes the most conserved locus; the RNA expression is highly tissue specific, e.g., bone marrow, immune cells, lung, liver, gall bladder, gastrointestinal tract and skin, while its protein expression is highly dependent on the cellular health status
While the highly polymorphic HLA-Ia molecules activate the immune system during pathogenic invasion, each HLA-Ib molecule is highly specialized in its expression profile and immune function
Expression of HLA-E on the cell surface avoids the recognition of HLA-Ia empty and viral infected cells by natural killer (NK) cells [33] through HLA-E-NKG2A interaction
Summary
HLA-F belongs to the family of HLA-Ib molecules and is of the whole HLA genes the most conserved locus; the RNA expression is highly tissue specific, e.g., bone marrow, immune cells, lung, liver, gall bladder, gastrointestinal tract and skin (https://www.proteinatlas.org), while its protein expression is highly dependent on the cellular health status. It could be demonstrated recently that HLA-F is able to select, bind and present peptides [3,4]; trimeric complexes of HLA-F heavy chain, β2m and peptide could be isolated following their assembly within the cells Those HLA-F bound peptides are of unusual length and the binding mode to the peptide binding region reveals an open end conformation without the classical pocket A or pocket B engagement; this observation explains the existence of HLA-F OCs. Structural and functional analysis illustrated that the engagement of HLA-F with its cognate NK cell receptor is dependent on the presence or absence of a bound peptide [3]. The functional impact of allelic mismatches on the protein and peptidome has not yet been comprehensively described
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