Stress proteins and other chaperones in antigenpresentation pathways

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hsp70

The ER-resident member of the hsp70 family, BiP, has been shown to associate with newly synthesized human (but not mouse) MHC class I molecules. It is unclear whether this association is important for the assembly of class I molecules, or whether the BiP:heavy chain complex is an intermediate on the way to heavy chain degradation in the ER. Similarly, MHC class II molecules synthesized in the absence of invariant chain associate with BiP prior to their intracellular degradation.

Antibodies raised to a unique, constitutively expressed member of the hsp70 family (PBP72/74) block MHC class II restricted antigen presentation. Although it is not clear how PBP72/74 is involved, the well-documented ability of hsp70 to bind peptides in an ATP-dependent way suggests that one way may be to protect or transport peptides prior to their association with MHC class II. A similar role has been suggested for cytosolic hsp70 in the chap-eroneing of peptides from their site of production (the proteasome) to the TAP transporter, although the evidence is extremely indirect and is based on the ability of hsp70-peptide complexes to induce pep-tide-specific CTLs.

hsp90

Both hsp90 and grp95 (as well as hsp70 - see above) purified from meth-A induced tumors can elicit MHC class I restricted CTLs which are specific for the tumors from which the hsps were purified. These CTLs actually recognize peptides which copurify with the hsps, in a class I restricted way, and this observation has led to the suggestion that hsp90 serves to chaperone these immunogenic peptides to an intracellular site where they can bind to class I. By extension, it has been suggested that grp90 may normally play a role in chaperoneing peptides arriving in the ER from the TAP transporter to awaiting MHC class I molecules.

Ubiquitin

The proteolytic events involved in generating antigenic peptides in the cytosol for presentation with MHC class I molecules involve the proteasome. This multicatalytic complex is responsible for disposing of ubiquitin-tagged proteins (see above), and the requirement for ubiquitination of cytosolic proteins destined for the MHC class I processing pathways has been implicated in a number of instances. For example, a temperature-sensitive Chinese hamster ovary (CHO) cell mutant of one of the ubiquitinating enzymes was able to present cytosolic antigens to

MHC class I restricted CTLs at the permissive, but not the nonpermissive temperature.

Calnexin and calreticulin

Although the ER-resident chaperone proteins calnexin and calreticulin are not stress proteins, they are included here for the sake of completeness. They bind to newly synthesized MHC class I heavy chains as they assemble with (32-microglobulin and retain them in the ER until they are fully assembled with antigenic peptides supplied by the TAP heterodimer.

Class II specific molecular chaperones: DM and li

Similarly, two proteins involved in the biogenesis of MHC class II-peptide complexes are included here even though they are not stress-induced. Invariant chain (Ii) prevents MHC class II molecules from aggregating in the ER; hinders their association with peptides in the ER; and specifically targets newly synthesized MHC class II molecules to the endosomal compartment. There it is degraded, leaving an Ii-derived peptide called CLIP bound in the MHC class II peptide-binding groove. The removal of this peptide, and its replacement with an antigenic peptide is facilitated by the MHC-like molecule DM which is itself encoded within the MHC class II locus.

See also: Adjuvant arthritis; Antigen presentation via MHC class I molecules; Antigen presentation via MHC class II molecules; Autoimmunity; ISCOM (immuno-stimulating complex); Molecular mimicry; Mycobacteria, infection and immunity; Rheumatoid arthritis, human; T cell vaccination.

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