Organization: Queen's University at Kingston
Date: Tuesday, 25 Aug 1992 13:24:28 EDT
From: <FORSDYKE@QUCDN.QueensU.CA>
Newsgroups: bionet.immunology
Subject: Re: Journal Watch: MHC and intracellular self
 <1992Aug24.181431.15117@news2.cis.umn.edu>
 <92237.151615FORSDYKE@QUCDN.QueensU.CA>
 <1992Aug25.134754.23844@news2.cis.umn.edu>

>>    Forsdyke:
>>                                     Donnan equilibrium. Now, if these
>>            collective functions were important from the viewpoint of
>>            evolutionary selection, then genes would be modified based on
>>            selection for these functions.

>     Prasad:
>I think this would be hard to argue from an evolutionary standpoint, because
>evolutionary changes usually, if not always, refer to modifications in
>protein function.  With hundreds (or thousands) of different proteins
>it is difficult to imagine how all these proteins would evolve, with
>consideration of all the others, to reach a certain final ?isotonicity? in
>the cytosol.

      Forsdyke: "Difficult to imagine"..Who said this was going to be easy?

>>            thus begin to define "self". The particular property of interest
>>            is that of protein concentration. Throughout evolutionary time
>>            each gene "fine-tunes" its protein concentration to the
>> collective pressure exerted by the other proteins with which it is moving
>>            through time. At the same time, all the proteins tend to maximize
>>            the collective pressure to drive individual proteins from        ,
>>   solution by pushing their own concentrations to the limit.  In this
>>            cytosolic environment, a not-self protein might more readily
>>            exceed its individual solubility limits. Thus is would aggregate
>>            and mark itself as foreign, thus fulfilling the criterion
>>            advanced earlier for its being conducted, via proteosomes, to the
>>            MHC protein complexes.
   Prasad:
>Where is the "right" protein concentration determined?  For those that are
>compartmentalized, is the proper concentration determined while they are
>being synthesized on the free ribosomes, or when they have reached their
> final compartment?

   Forsdyke: Determination is at the gene level, where factors such as
             transcription rates, mRNA stability, protein stability..are
             encoded. The evolutionary input into the gene sequences is
             determined by the phenotype (=protein concentration in the
             cytosol,..to pick the most obvious "final compartment")
   Prasad:
                Although it may be logical, it is more difficult to
>experimentally determine how evolution determines the final protein
>concentration.  Are there any references on this?
>
   Forsdyke: Food for thought in this respect is provided by McConkey, E.H.
             (1982) Proc.Natl.Acad.Sci.USA 79, 3236-3240. "Molecular evolution,
             intracellular organization and the quinary structure of proteins."
   Prasad:

>As far as viral protein solubility limits, viruses too are highly evolved
>to be as efficient as possible.

   Forsdyke: Contradiction in terms? Efficient for what? The raison d'etre
             of a virus is, in your words, to "care
>less about staying below the solubility limits, as its GOAL is to produce
>viral proteins, package its nucleic acid, and lyse the cell, all before
>an immune response can destroy the infected cell.

   Forsdyke: The solubility limit imposes a restraint, which the virus has to
             evolve to cope with. But if the virus wants to increase in
             number, it may more readily exceed the limit than self-proteins.
             Thus, the cell becomes marked for T cell attack.
   Prasad:
>If a certain viral protein exceeds its solubility limit, then it may be at
>a concentration that outcompetes self proteins for MHC binding.
>
>This type of self-nonself discrimination does not exclude self proteins
>from presentation.

   Forsdyke: The exclusion of self-proteins is what we are talking about.
             That does not mean that the exclusion system must be perfect.
             Deleting certain autoreactive T cell species would allow some
             self peptides to be presented at the cell surface without T cell
             attack.
               Here we come to the heat-shock response. This response increases
             the cytosolic concentration of the heat-shock proteins, thus
             increasing the chances that peptides from these self proteins
             might be displayed at the cell surface. However, the heat-shock
             response also involves a DECREASE in concentration of many self
             proteins, thus decreasing the chances that peptides from these
             proteins would be displayed. (Forsdyke, 1985; Ohno, 1992).
   References:
               Forsdyke, D. (1985) J. Theoret.Biol. 115, 471-473.
               Ohno, S. (1992) Immunogenetics 36, 22-27.
>>>>>>>>>>>>              Prasad, S. (1992) Bionet.immunology 814 1516gmt
>>>>>>>>>>>>              Forsdyke, D. (1992) Bionet.immunology 817 1757edt
>>>>>>>>>>>>              Prasad, S. (1992) Bionet.immunology 818 133gmt
>>>>>>>>>>>               Forsdyke, D. (1992) Bionet.immunology 818, 1616edt
>>>>>>>>>>                Prasad, S. (1992) Bionet.immunology 819, 405gmt
>>>>>>>>>                 Forsdyke, D. (1992) Bionet.immunology 819 1019edt
>>>>>>>>>                 Prasad, S. (1992) Bionet.immunology 819, 2019gmt
>>>>>>>                   Forsdyke, D. (1992) Bionet.immunology 820, 858edt
>>>>>>>>                  Prasad, S. (1992) Bionet.immunology 821, 56gmt
>>>>>                     Forsdyke, D. (1992) Bionet.immunology, 821, 858edt
>>>>>                     Prasad, S. (1992) Bionet.immunology 821, 1544gmt
>>>                       Forsdyke, D. (1922) Bionet.immunology 824, 918edt
>>>                       Prasad, S. (1992) Bionet.immunology 824, 1814gmt
>                         Forsdyke, D. (1992) Bionet.immunology 824, 1416edt
>                         Prasad. S. (1992) Bionet.immunology 825, 1347gmt