HLA-F

This gene belongs to the HLA class I heavy chain paralogues. It encodes a non-classical heavy chain that forms a heterodimer with a beta-2 microglobulin light chain, with the heavy chain anchored in the membrane. Unlike most other HLA heavy chains, this molecule is localized in the endoplasmic reticulum and Golgi apparatus, with a small amount present at the cell surface in some cell types. It contains a divergent peptide-binding groove, and is thought to bind a restricted subset of peptides for immune presentation. This gene exhibits few polymorphisms. Multiple transcript variants encoding different isoforms have been found for this gene. These variants lack a coding exon found in transcripts from other HLA paralogues due to an altered splice acceptor site, resulting in a shorter cytoplasmic domain.

Full Name

Major Histocompatibility Complex, Class I, F

Function

Non-classical major histocompatibility class Ib molecule postulated to play a role in immune surveillance, immune tolerance and inflammation. Functions in two forms, as a heterotrimeric complex with B2M/beta-2 microglobulin and a peptide (peptide-bound HLA-F-B2M) and as an open conformer (OC) devoid of peptide and B2M (peptide-free OC). In complex with B2M, presents non-canonical self-peptides carrying post-translational modifications, particularly phosphorylated self-peptides. Peptide-bound HLA-F-B2M acts as a ligand for LILRB1 inhibitory receptor, a major player in maternal-fetal tolerance. Peptide-free OC acts as a ligand for KIR3DS1 and KIR3DL2 receptors (PubMed:28636952).

Upon interaction with activating KIR3DS1 receptor on NK cells, triggers NK cell degranulation and anti-viral cytokine production (PubMed:27455421).

Through interaction with KIR3DL2 receptor, inhibits NK and T cell effector functions (PubMed:24018270).

May interact with other MHC class I OCs to cross-present exogenous viral, tumor or minor histompatibility antigens to cytotoxic CD8+ T cells, triggering effector and memory responses (PubMed:23851683).

May play a role in inflammatory responses in the peripheral nervous system. Through interaction with KIR3DL2, may protect motor neurons from astrocyte-induced toxicity (PubMed:26928464).

Biological Process

Antigen processing and presentation of endogenous peptide antigen via MHC class Ib Source: UniProtKB
Antigen processing and presentation of exogenous peptide antigen via MHC class Ib Source: UniProtKB
Antigen processing and presentation of peptide antigen via MHC class I Source: UniProtKB-KW
Negative regulation of natural killer cell cytokine production Source: UniProtKB
Negative regulation of natural killer cell degranulation Source: UniProtKB
Negative regulation of natural killer cell mediated cytotoxicity Source: UniProtKB
Negative regulation of neuron death Source: UniProtKB
Negative regulation of T cell cytokine production Source: UniProtKB
Positive regulation of natural killer cell cytokine production Source: UniProtKB
Positive regulation of natural killer cell degranulation Source: UniProtKB
Positive regulation of T cell mediated cytotoxicity Source: UniProtKB

Cellular Location

Lysosome membrane; Early endosome membrane; Cell membrane. For cross-presentation transits from the cell surface through endosomal pathway to lysosomes, where the peptide is generated from internalized exogenous antigen.

Topology

Extracellular: 22-305
Helical: 306-329
Cytoplasmic: 330-346

PTM

N-glycosylated.