HELP with PROTEASOMES and ANTIGEN PRESENTATION

Ian A. York iayork at panix.com
Sun Dec 22 15:27:31 EST 1996


In article <59k411$mh8 at camel4.mindspring.com>,
Richard A. Lockshin <lockshin at mindspring.com> wrote:
>Undergraduate research is really best done in the library--internet
>
>>My name is John and I am an undergraduate senior biology student at
>>Philadelphia College of Pharmacy and Science.  I am need of IMMEDIATE
>>RESPONSE regarding any answers to any of the following questions. 

I didn't respond to this, partly because I was busy at the time and partly
because it looked as if someone might be looking for answers for an exam; 
as Rischard says this sort of research is best done at the library. 
Anyway, since I now have a bit of time on my hands and since this isn't
likely to be of any help for an exam any more anyway, here are a few
comments.

>> -the role of ubiquination in antigen processing

As far as I know, there's nothing brand new on this.  The evidence is
suggestive, but not definitive, that ubiquitination is involved in peptide
generation for class I antigen presentation.  This comes from a number of
observations, including a mutant cell line with a temperature-sensitive
ubiquitination pathway, which had reduced antigen presentation at the
non-permissive temperature (Michalek et al, Nature 363:552-4, 1993); and
from the observation that the N-end rule (which affects the rate at which
ubiquitin-proteasome pathways degrade proteins) alter the rate of
presentation (Grant et al, J. Immunol.  155:3750-8, 1995).  Not everyone
agrees with these observations; see especially Cox et al, J. Immunol.
154:511-9, 1995 (but look closely at the figures in this papers; they may
actually show some effect after all).  

>> -the importance of IFN-gamma

Upregulates, essentially, all the components of antigen processing and
presentation.  Difficult to sort out individual effects.

>> -the importance of LMP-2 and/or LPM-7 

Again there's nothing brand new that I know of.  Both are beta-type
subunits of the proteasome - i.e. they're catalytically active - and
evidence from knockout mice (other sources as well, but the knockouts are,
I think, by far the most convincing) suggest that they have a role in
antigen processing - mice lacking either LMP2 or LMP7 have defects in CTL
maturation and/or MHC class I surface expression, and have more or less
subtle changes in the type of peptide generated.  For the KO mice, see
Fehling et al, Science 265:1234-7, 1994 and Van Kaer et al, Immunity
1:533-41, 1994.  There are seveal papers that look at the altered
specificity of the proteasome when LMP2/7 are present - to summarize,
there is a trend to production of peptides which are more likely to bind
to MHC class I.  See, for example, Stohwasser et al, FEBS Let.
383:109-113, 1996 and Gaczynska et al, J Biol Chem 271:17275-80, 1996.  

>> -enzymes that trim antigenic peptides to their final length on MHC
>>molecules

This is a mildly controversial issue.  I think the general opinion - well,
my opinion, anyway - is that once peptides bind to MHC class I they are
not trimmed frther.  The original suggestion was an attractive idea to
account for the snug fit of peptides and the apparently rare overhangs.
However, not only has it been shown that there are, in fact, a fair number
of overhanging peptides in surface class I (e.g. in HLA-B27, I think it
is), but the crystal structure of class I, according to Strominger and
Wiley (this is from memory, I don't have the reference beside me),
wouldn't allow an enzyme room to trim back to the final peptide.  Probably
the majority of peptides are generated in the cytoplasm, either by the
proteasome alone or by the proteasome and other enzymes, and are not
modifed after binding the class I in the ER.

>> -MHC class I loading versus MHC class II loading

Too much to even try to sumamrize.

>>What are some of the potential applications of proteasomal/antigen
>>research? Cancer? Viral diseases? Transplants?  How distant in the
>>future is such application?

Who knows?  If proteasome is essential, conceivably blocking it would
reduce antigenicity.  Of course, if the proteasome is completely blocked
the cell dies, so you're not necessarily much further ahead.  LMP2/7,
while enhancing the generation of antigenic peptides, are not essential,
so they don't provide an absolute handle.  Use your imagination ...

You might be interested in our review
 York, I.A., and K.L. Rock.  (1996).  Antigen processing and presentation
by class I MHC.  Annu. Rev. Immunol.  14:369-396. 

Since much of the work implicating proteasome in antigen presentation has
been done in our lab, the review is probably moderately biased towards
proteasome.  Not everyone agrees with this emphasis.  

Ian
-- 
      Ian York   (iayork at panix.com)  <http://www.panix.com/~iayork/>
      "-but as he was a York, I am rather inclined to suppose him a
       very respectable Man." -Jane Austen, The History of England



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