UniProt functional annotation for P04233



	UniProt functional annotation for P04233

UniProt code: P04233.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF.

Function: [Class-II-associated invariant chain peptide]: Binds to the peptide-binding site of MHC class II alpha/beta heterodimers forming an alpha-beta-CLIP complex, thereby preventing the loading of antigenic peptides to the MHC class II complex until its release by HLA-DM in the endosome. {ECO:0000269|PubMed:1448172}.

Function: [Isoform p41]: Stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of antigen-presenting cells (APCs). Has antiviral activity by stymieing the endosomal entry of Ebola virus and coronaviruses, including SARS-CoV-2 (PubMed:32855215). Disrupts cathepsin-mediated Ebola virus glycoprotein processing, which prevents viral fusion and entry. This antiviral activity is specific to p41 isoform (PubMed:32855215). {ECO:0000250|UniProtKB:P04441, ECO:0000269|PubMed:32855215}.

Subunit: Homotrimer. In the endoplasmic reticulum (ER) it forms a heterononameric MHC II-Ii complex: 3 MHC class II molecules (heterodimers of an alpha and a beta subunit) bind to the CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system, the CD74 component undergoes sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide) attached to the MHC class II molecule (alpha-beta-CLIP complex). This processed complex interacts with HLA_DM and HLA_DO heterodimers in order to release CLIP and facilitate the binding of antigenic peptides to the MHC class II molecules. Interacts with CD44; this complex is essential for the MIF- induced signaling cascade that results in B cell survival. {ECO:0000250|UniProtKB:P04441, ECO:0000269|PubMed:12782713, ECO:0000269|PubMed:7477400}.

Subunit: [Isoform p41]: Interacts with the mature form of CTSL; the complex survive in neutral pH environment. {ECO:0000269|PubMed:10022822}.

Subcellular location: Cell membrane {ECO:0000305}; Single-pass type II membrane protein {ECO:0000305}. Endoplasmic reticulum membrane. Golgi apparatus, trans-Golgi network. Endosome. Lysosome. Note=Transits through a number of intracellular compartments in the endocytic pathway. It can either undergo proteolysis or reach the cell membrane.

Subcellular location: [Isoform p41]: Late endosome {ECO:0000250|UniProtKB:P04441}. Lysosome {ECO:0000250|UniProtKB:P04441}.

Tissue specificity: [Isoform p41]: In B cells, represents 10% of total CD74 expression. {ECO:0000269|PubMed:3104027}.

Tissue specificity: [Isoform p33]: In B cells, represents 70% of total CD74 expression. {ECO:0000269|PubMed:3104027}.

Domain: Antiviral activity requires delivery of the thyroglobulin domain to the endosomal membrane. {ECO:0000269|PubMed:32855215}.

Ptm: N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. {ECO:0000269|PubMed:10022822, ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22171320, ECO:0000269|PubMed:23234360}.

Disease: Note=A chromosomal aberration involving CD74 is found in a non-small cell lung tumor. Results in the formation of a CD74-ROS1 chimeric protein. {ECO:0000269|PubMed:12661006}.

Sequence caution: Sequence=AAA36304.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF.



Function:		[Class-II-associated invariant chain peptide]: Binds to the peptide-binding site of MHC class II alpha/beta heterodimers forming an alpha-beta-CLIP complex, thereby preventing the loading of antigenic peptides to the MHC class II complex until its release by HLA-DM in the endosome. {ECO:0000269\|PubMed:1448172}.



Function:		[Isoform p41]: Stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of antigen-presenting cells (APCs). Has antiviral activity by stymieing the endosomal entry of Ebola virus and coronaviruses, including SARS-CoV-2 (PubMed:32855215). Disrupts cathepsin-mediated Ebola virus glycoprotein processing, which prevents viral fusion and entry. This antiviral activity is specific to p41 isoform (PubMed:32855215). {ECO:0000250\|UniProtKB:P04441, ECO:0000269\|PubMed:32855215}.


Subunit:		Homotrimer. In the endoplasmic reticulum (ER) it forms a heterononameric MHC II-Ii complex: 3 MHC class II molecules (heterodimers of an alpha and a beta subunit) bind to the CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system, the CD74 component undergoes sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide) attached to the MHC class II molecule (alpha-beta-CLIP complex). This processed complex interacts with HLA_DM and HLA_DO heterodimers in order to release CLIP and facilitate the binding of antigenic peptides to the MHC class II molecules. Interacts with CD44; this complex is essential for the MIF- induced signaling cascade that results in B cell survival. {ECO:0000250\|UniProtKB:P04441, ECO:0000269\|PubMed:12782713, ECO:0000269\|PubMed:7477400}.
Subunit:		[Isoform p41]: Interacts with the mature form of CTSL; the complex survive in neutral pH environment. {ECO:0000269\|PubMed:10022822}.
Subcellular location:		Cell membrane {ECO:0000305}; Single-pass type II membrane protein {ECO:0000305}. Endoplasmic reticulum membrane. Golgi apparatus, trans-Golgi network. Endosome. Lysosome. Note=Transits through a number of intracellular compartments in the endocytic pathway. It can either undergo proteolysis or reach the cell membrane.
Subcellular location:		[Isoform p41]: Late endosome {ECO:0000250\|UniProtKB:P04441}. Lysosome {ECO:0000250\|UniProtKB:P04441}.
Tissue specificity:		[Isoform p41]: In B cells, represents 10% of total CD74 expression. {ECO:0000269\|PubMed:3104027}.
Tissue specificity:		[Isoform p33]: In B cells, represents 70% of total CD74 expression. {ECO:0000269\|PubMed:3104027}.
Domain:		Antiviral activity requires delivery of the thyroglobulin domain to the endosomal membrane. {ECO:0000269\|PubMed:32855215}.
Ptm:		N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. {ECO:0000269\|PubMed:10022822, ECO:0000269\|PubMed:19159218, ECO:0000269\|PubMed:22171320, ECO:0000269\|PubMed:23234360}.
Disease:		Note=A chromosomal aberration involving CD74 is found in a non-small cell lung tumor. Results in the formation of a CD74-ROS1 chimeric protein. {ECO:0000269\|PubMed:12661006}.
Sequence caution:		Sequence=AAA36304.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};