The function of proteasome in immunity

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jws
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The function of proteasome in immunity

My first question is that It is well known that proteasome processes the degradation of proteins which facilitate antigen presentation. How can proteasome specifically degrade viral or cancer products without harming the housekeeping proteins?
My second question is that how the cells sense infection of DNA viruses.
 
Thank you.

heehawmcduff
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As a start to this, this
Ivan Delgado
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Hi jws,

Hi jws,
This is a very broad question. One could start by explaining that when you are born one the main reasons why it is important to receive your mother's milk is that it is full of antibodies your body needs as it puts together its own immune system. Since viral and cancer proteins are not present at this stage (hopefully) your body does not recognize them as part of your self. As a result when these infect you later in life they are recognized as foreign and thus attacked.
As for how cells identify infection, look for adaptive immune system, lymphocytes, and B and T cells. That should get you started. Also, one of the coolest molecular genetic topics is how your body re-arranges the genes that make up antibodies (the so called V, D, and J genes) in order to be able to recognize thousands of foreign molecules. An amazing machinery indeed.

R Bishop
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Along the lines of what Ivan

Along the lines of what Ivan is saying, the proteasome is degrading self proteins, they simply aren't recognized as 'foreign' antigens. This process is not harmful per se since cells are doing it all the time.
 
As far as reconizing infection by DNA viruses, from my grad school days (8yrs ago) i seem to remember its along the same lines, the viruses produces proteins that are not recognized as self by the immune system.  This is one reason why virus co-opt the ER-golgi pathway to glycosylate their foreign looking proteins.   Otherwise I suppose the cell "knows" or "senses" its systems are not functioning correctly (i.e., house keeping genes are not being transcribed/translated, etc), which sends them down the apoptosis route.
 
Sorry for the generalties, but it is sort of fascinating to think about it.
 
Rus

Jen_Floyd
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 Also TLR3, 7,  8, and 9

 Also TLR3, 7,  8, and 9 recognize nucleic acids and activate the immune system through interferons.

varsha
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jws wrote:

jws wrote:

My first question is that It is well known that proteasome processes the degradation of proteins which facilitate antigen presentation. How can proteasome specifically degrade viral or cancer products without harming the housekeeping proteins?
My second question is that how the cells sense infection of DNA viruses.
 
Thank you.

Hi jws.
Proteasome and lysomoes are two major proteins degradation structures/compartments in the cell. While lysosome is mostly targeted for membrane proteins, receptor-mediated endocytosed and phagocytosed proteins, Proteasome deals with a large number of endogenous as well as foreign proteins. The susbstraes include:
1) misfolded or truncated proteins
2) damaged proteins e.g during oxidative stress
3) temporally required proteins e.g. cyclins during specific phases of  cell cycle
4) antigen presentation substrates which include viral and parasitic proteins or some cancer proteins
Proteasomes recognize their substrates if they have a tag called ubiquitin, a 76 residue protein. In a polyubiqutination event, multiple ubiquitin units are added onto Lysine side chain of intended substrates through the action of E3 ubiquitin ligase (monoubiquitination, on the other hand, can affect subcellular localization and activity of some substrates).

There are hundreds of E3 ligases inside the cell and many of them are substrate specific. It makes sense to have a specific E3 ligase for a protein whose activity needs to be modulated quickly e.g. a cyclin during cell cycle or a oxidative stress-induced transcription factor when the recovery is complete.
Inhibition of proteasome function for prolonged periods can cause cell death- Anti-cancer chemotherapy drug, Bortezomib, causes apoptosis of cancer cells. Anti-HIV drug, ritonavir is another protesome and protease inhibitor.
The ubiquitin system, disease, and drug discovery
Inhibition of protesome could be harmful in other scenarios. For example, several genetic disorders are caused by E3 ligase mutaion- Angelman syndrome, Von Hippel-Lindau syndrome, Liddle's Syndrome, Fanconi anemia etc. Neurofibrillary tangles in Alzhimer's disease and Lewy bodies in PD are ubiquitin posotive, underscoring the importance of timely protein degradation. Many other neurodegenerative diseases arise from protein aggregation which donot get clered by the protein degradation system of the cell.
There are other ubiquitin like tags e.g SUMO, NEDD8 etc which appear to play a role in protein degradation, subcellular localization and activity. Most housekeeping genes are not tagged with ubiqutin or other modifiers unless they have sustained a damage or got misfolded during, let's say heat shock. This protects them from degradation while the tagged ones get digested.

jws
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Thank you for responses.

Thank you for responses.
I am wandering if proteasome degrades most of the proteins inside cells constantly. Unbiquitated proteins are targeted for fast degradation. Is it possible that proteasome also continuously degrades most cellular proteins which helps maintain the amount of cell proteins since new proteins are simultaneously synthesized? With this mechanism, the proteasome has chance to degrade viral products for antigen presentation since proteasome has no ability to differentiate and preferentially digest viral products. I am also wandering whether the interference of synthesis of a specific cellular products like mRNA or proteins would enhance the recognition of viral infection.
The final question is that cancer cells sometimes have tumor marker or specific proteins on their surface. Why cytotoxic T cells can not kill tumor cells is due to the inactivation of apoptosis. Since the cause of tumor is accumulation of malfunction of several different genes, is it possible that some tumor has no different proteins with mutation but has only malfunctional gene regulators like promoters which causes the difference in protein expression level and increases the difficulty for being recognized by our immune system?