Journal Watch: MHC and intracellular self
FORSDYKE at QUCDN.QueensU.CA
FORSDYKE at QUCDN.QueensU.CA
Tue Aug 25 12:24:28 EST 1992
>> 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.
>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
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.
>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")
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."
>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.
>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
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
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).
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
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