You must be logged in to vote!
catch-22
Another way to approach it is to think about MHC class I processing. Basically, if you inhibit the proteasome, peptides will not be generated and nothing is available to be loaded onto MHC I (remember MHC I has to be loaded before it's transported to the cell surface). Cells that don't express MHC I get killed by the natural killers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2214736/
+32
kai
"In conclusion, we have demonstrated that the proteasome inhibitor bortezomib down-regulates class I and enhances the sensitivity of myeloma to NK cellโmediated lysis" from the conclusion of the NIH paper
+6
maddy1994
another mechanism is by blocking proteosome u even decrease degration of proapoptotic proteins...so it enchances apoptosis(from uworld)
+6
azibird
But CD8+ and NK cells kill via perforin! Why is this answer wrong? Is it because it's not the primary effect?
+2
testready
"The proteasome is the major source of proteolytic activity involved in the generation of peptides for presentation by major histocompatibility complex class I molecules. We report the new observation that bortezomib down-regulates HLA class I on MM cells, resulting in increased NK cellโmediated lysis."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2214736/
+
fatboyslim
I think what OP said contradicts with what @catch-22 cited in the PubMed article.
+
an1
OP said "Only by expression of the proteasome, or its over-expression, can these mutant proteins be degraded fast enough to not be displayed by MHC I". UW QID 11674 says that a protein undergoes degradation by the ubiquitin proteasome pathway, after which it goes to the ER and then is presented to the cell surface for MHC 1 response leading to apoptosis via performs and granzymes. Having a proteasome inhibitor would actually prevent the MHC response because no proteins are displayed. Also note that the question says which process will be affected, there is no mention of increase or decrease. So yes, the MHC 1/ CD8 pathways is affected, but it's actually down regulated. An absence of MHC 1 leads to NK cell mediated death.
+
"Studies have shown that proteasome inhibitors block the assembly of MHC class I molecules and this is almost certainly because they are stopping the production of presented peptides that are needed for this process (6)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094101/
You must be logged in to vote!
You must be logged in to vote!
ergogenic22
Bortezomib does not directly activate perforin. It directly inhibits the proteasome which โ enables CD8+ T cells to initiate apoptosis โ via perforin release (in essence a downstream effect).
+4
drzed
Exactly, it triggers the cells to undergo apoptosis which means that it can either be cell mediated (perforin and granzyme via FAS/FASL) OR it could also be through the intrinsic pathway (e.g. mitochondrial; cytochrome c)
+
powerhouseofthecell
Question: But how do CD8 cells have a role in this process exactly in the vignette? Is it saying that when the proteins build up, only then do CD8 cells come and instead of MHC I presenting to proteasomes, they present it to CD8 to initiate apoptosis?
+
flexatronn
@powerhouseofthecell
so it all goes back to basic immuno (i got this wrong and put apoptosis as well) but after reviewing relevant anki cards, i now get it.
So proteasomes break down tagged proteins within the cell (endogenous). The breakdown products get taken up by transport associated with antigen processing (TAP) and brought to the rough ER. The breakdown products are then loaded onto MHC I molecules and brought to the surface of the cell. When thinking about MHC I, think about CD8+ T cells (FA MHC 1 x 8 = CD8.
Now to summarize, when using a proteasome inhibitor, you're blocking that tagging and MHC I loading process. As stated before, CD8 recognizes MHC I (which won't happen when using these drugs)
+3
You must be logged in to vote!
tyrionwill
under Bortezomib, the proteasome cannot digest viral Ag and presents it to the membrane-bonded MHC-I. Therefore CD8-Tc cannot recognize the host cells containing relapsed VZV. That is probably why shingles is one of the popular side effect of Bortezomib.
+
kcyanide101
The drug inhibits proteosome. Hence there is no fragment available through TAP inside CD4 cell to load unto MHC I.... As such the CD8 presentation to Tcell is prevented. The accumulating proteins inside the CD8 cells which are not being broken down by the proteosome cause it to undergo apoptosis
+
You must be logged in to vote!
submitted by โsajaqua1(607)
MHC I function is integral to cancer suppression. MHC I displays endogenously synthesized proteins and presents them to CD8+ T cells. The failure to display MHC I, or MHC I display of non-self (and by extension cancerous) proteins triggers a cellular immune response, leading to destruction of the cell.
The proteasome is used for the degradation of worn out, senescent, or malformed proteins. As cancer develops, more mutations lead to increased wrong proteins. Only by expression of the proteasome, or its over-expression, can these mutant proteins be degraded fast enough to not be displayed by MHC I and lead to the cell being killed. Bortezomib blocks the proteasome, so the mutant proteins are displayed on the surface, allowing the immune system to recognize and kill pathological cells.