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"The SARS-CoV-2 S protein on the membrane of infected cells can promote receptor-dependent syncytia formation, relating to extensive tissue damage and lymphocyte elimination." Liu Wenzhong, Li Hualan, 2021, pubmed

Is it understood that this expression of protein on the cell membrane of infected cells is to be distinguished and is different from presentation of that same protein within the MHC-cleft for immunization/priming purposes?

Simply said: the protein inducing syncytia formation is not presented within the Major histocompatibility complex but a (non-immunizing) "stand alone"?

(Only) one more reference I was able to find:

"In several coronaviruses, S protein that does not get assembled into virions transits to the cell surface where it mediates cell–cell fusion between infected cells and adjacent, uninfected cells."

Fehr/Perlman: Coronaviruses: An Overview of Their Replication and Pathogenesis (2015, "Protocol, Part of the Methods in Molecular Biology book series")

From this it might appear that presentation on cell surface is not within the MHC (thus not attracting T cytotoxic cells). Is that correct, is there any more reference?

Having received two answers it has become clear that this question should be split in two: 1. Is spike protein expressed as some regular cell membrane proteine by infected cells when inducing syncytia or is the protein expressed within the immunizing MHC? 2. If protein is expressed outside MHC does this exclude any presentation on MHC (as the cell considers itself in a regular state, of syncytia production that is). I consider 2 a new, different question, and mingling that in the question 1 asked seems confusing.

2 Answers 2

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I'm not sure on your question - the protein produced from translation of the viral mRNA is all the same. Vast quantities are produced to generate the amounts needed to make up the numerous progeny virions. Some of this protein will end up at the cell surface, some will end up on the MHC, but it is all the same protein.

There is no differentiation during production that specifically targets any protein to the MHC.

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    Indeed, it seems "to be understood" - being ironic? Please add any reference there is, any basic textbook if there is, I am badly in need of some reference. Thank you! Commented Jan 4, 2022 at 16:45
  • @PeterBernhard molecular biology of the cell might be a good starting point. Chapter 6 would be your best for DNA -> protein.
    – bob1
    Commented Jan 4, 2022 at 20:37
  • I read through. Question is not on basic cell biology but on viral mechanisms of infection, though. Need specific reference for what might just be a lack of positive search results - any authority that explicitly says that "there is no" (differentiation)? Any antigen being presented on MHC to, t-cytotoxic cells also becomes regular, integral part of the infected cell's membrane? Pease add specific reference (from "The cell", topic is from "virology", though) for your stating that viral proteins are being expressed on the membrane with AND without MHC (that it's not MHC ONLY). Thanks. Commented Jan 5, 2022 at 10:35
  • @PeterBernhard hard to prove a negative! Our understanding of how RNA -> protein tells us that the mechanism doesn't change the output be it from viral or cellular RNA (in CoV these both use the cell machinery...). There may be some immature or partial products that make it onto the MHC, but for the most part the proteins are full length mature products that get sent to the cell membrane for virion production. They don't become an integral part of the membrane, MHC associated or not, because the cell gets killed by the virus eventually.
    – bob1
    Commented Jan 5, 2022 at 21:56
  • "There is no differentiation during production..." - that's what you refer to replying "hard to prove the negative", correct? I guess you didn't advise me "enough" on the basic mistake I made with full lenght protein (Armand had to and did). On the other hand, thank you for your instant empathy for what "really" interests me: How does viral membrane relate to MHC. Could there be even be some either/or, i.e. the more whole protein the less MHC expression (which might interestingly refer to "missing self" of cancer immunology). Any reference for "not regulated"? Commented Feb 12, 2022 at 19:20
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I'm not fully sure I understand your question but I believe the answer is "yes", that the syncytia-inducing S proteins are different from the S protein fragments presented by MHC molecules.

Remember, in the antigen presentation pathway, some proteins are cleaved into peptide fragments inside the cell, then those peptides bind to MHC molecules and those complexes migrate to the cell membrane.

On the other hand, I believe full-size functional S proteins make their way to the cell membrane, and in sufficient numbers may cause the cell membrane to fuse with that of adjacent cells, creating a syncytium. This is not related to the antigen presentation pathway.

So, just one source of translation producing S proteins, but (most) proteins end up in virions or in cell membrane, while some after translation are grabbed by the antigen presentation pathway, cut up and resulting fragments complexed with MHC then end up on cell surface for presentation. Both "normal" production of S proteins and diversion of a few to the antigen-presentation pathway happen at the same time in the same cell.

Re: "inducing syncitia by spike has got nothing to with MHC-presentation. " Yes, that's right. Syncitia formation involves multiple full S proteins (the functional unit is actually 3 S proteins complexed together). MHC presentation in general presents such tiny protein fragments of just one protein that they shouldn't have functional activity on their own.

This YouTube video may be helpful: https://youtu.be/QsMaTgCf_aY "Antigen Processing and Presentation (PART I): MHC I Antigen Presentation pathway (FL-Immuno/25)"

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  • But it is still the same protein - just fragments of the mature I believe? I could easily be wrong on that though, not having any immunology background.
    – bob1
    Commented Jan 10, 2022 at 19:56
  • Yes, some of the proteins get grabbed by the presentation pathway, which chops them up into peptides, and those peptides (maybe 10 aa long?) complex with MHC, with the complexes then being exposed on the cell surface. The peptides are way too small to have any of the original S function.
    – Armand
    Commented Jan 10, 2022 at 21:17
  • "syncytia-inducing S proteins are different from the S protein fragments presented by MHC molecules." fused to "some proteins are cleaved into peptide fragments" made my up vote for today. Helpful! The former, I read maybe like bob1 did: I skipped the word "fragment", as that's what's bothering me right now: are there different isotypes of the spike, is there some "syncitial" isotype, that's what bob1 might allude to in his comment. Armand's answer's focus is onto that crossroad of pathways: simply said, what decision is it that determines if whole spike protein is cleaved/MHCed or not? Commented Jan 11, 2022 at 10:37
  • I added Peter's specific assertion to the end of the answer. As to choice of pathways for a given protein molecule, my understanding is that the presentation pathway is constantly sampling from all the proteins being translated by the cell, perhaps like a factory randomly checking a few newly-made units on the assembly line to monitor quality.
    – Armand
    Commented Jan 11, 2022 at 22:09
  • Armand's linked video, at 4:22, shows the "proteasome" taking up output from viral DNA/RNA (as if the virus came in for this, to hand over). Good hint! Interestingly, the video is not very clear on distinguishing presentation within MHC ("tiny desk") from presentation as a regular membrane protein, inducing syncytia. That question seems is still unanswered. Can you give reference for "...my understanding is that the presentation pathway is constantly sampling..." Video maybe misleading: proteasome completely distroys, does not present? Commented Feb 10, 2022 at 19:06

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