- Hello all, I have some fairly specific questions about the MHC I pathway I am having difficulty answering from the literature and was hoping that I might please get some clarity...
- Doctrine argues that cytosolic and ER proteins end up on MHC I, not nuclear proteins. To me, this seems unlikely as many viruses (HIV, HPV, HCV, etc) make many strictly nucleophilic proteins, and many of the most critical oncoproteins found in cancer cells are confined to the nucleus. The nucleus also has its own proteosomes, and was wondering if there is any evidence of peptides derived from strictly nuclear proteins being expressed on MHC I?
- How do E3 ligases "choose" which proteins they will attach a ubiquitin/polyubiquitin chain to? I understand that ubiquitin is attached to lysine residues on proteins (and possibly other amino acids in non-canonical ubiquitination), but is this process random, or are proteins somehow marked for ubiquitin attachment in the cytosol?
- Since the entire MHC machinery is essentially a quality control program that provides a safegaurd against mutation, is it possible that nascent proteins may become ubiquitinated co-translationally?
- Incorrectly folded and viral peptides/mutated proteins end up on MHC I, but do peptides derived from correctly folded, non-mutated proteins also end up on MHC I as well? The way I was taught was that this entire pathway is essentially a quality control program that operates as a part of a largely random process of protein sampling that coincides regular protein turnover? In other words, can a correctly folded cytosolic protein that has served its purpose be degraded via proteosome and end up on MHC I?
- The peptide binding groove of the MHC I complex must accommodate peptides derived from self as well as non-self peptides, such as from viruses and mutated proteins. How does this site conform to peptides of differing amino acid composition and size? (eg do the proteins of MHC I complexes undergo some type of recombination or somatic hypermutation such as in B-/T-cell receptors?)
- any response and or resources given would be greatly appreciated. Thanks in advance for your answers.
I have just a couple of general answers for you.
1. While the proteosome is in the cytosol, it will process anything that is in there, regardless of how it gets there. Originally, people thought that MHC II peptides and MHC I peptides don't cross, but they do. Vesicles are leaky, and in MTB, the phagosome will leak MTB proteins into the cytosol. And vice versa, during the development of the autophagosome, that can scoop up cytosol proteins and get processed into MHC II.
2. MHCs do not undergo recombination events. (That I know of...)
I was also wondering about the antigenicity of T and B cell receptor antigens. Both of these receptors undergo recombination or somatic mutation, generating novel peptides in the hypervariable regions that are not found in the proteomes of somatic cells. Since these receptors are both membrane/cytoplasmic proteins, they must also be degraded and processed on MHC I to some extent. These millions of possible combinations of antigens thus could not be expressed by AIRE in the thymus, so why are these antigens from hypervariable regions not recognized by other T cells via MHC I?
Brett Carter My first thought is that paratope peptides are not "too antigenic" to be recognized, or maybe MHC I molecules don't fit those peptides. Another thing is inhibitory molecules that would prevent response even if they are recognized. Finally, even if the peptides are not expressed by AIRE, they are still expressed in the thymus during T cell development, so there may be a probability that maturating T cells that react to their peers in thymus are negatively selected. All of the above are just my speculations though.
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