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.
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.