The COVID-19 coronavirus SARS-CoV-2 enters cells by receptor-mediated endocytosis. See, e.g. here.
Why doesn’t the enzyme ACE2 — SARS-CoV-2’s target receptor — undergo endocytosis when bound by its physiological ligand, angiotensin II? If ACE2 triggers endocytosis on binding SARS-CoV-2, why doesn’t it trigger endocytosis on binding its physiological ligand?
For instance, from https://www.nature.com/articles/cr200815 I know what receptor-mediated endocytosis is. However, I just cannot imagine just the opposite, in my wording: non-receptor mediated (endocytosis). My guess is that the virus contacts a receptor and gets endocytosed, however I imagine the receptor as being left behind, on the membrane, where it remains, it's just some anchor. In other words: does there exist some mechanism that uses a receptor for attaching the virus like a rod to get - not the spike but - the virus membrane close to the membrane of the cell so fusion of membranes might happen. Would that be endocytosis, fusion of membranes?
Some idea to get into it deeper, so to speak: ACE2 is special as it's an enzyme - and it does not have, alternatively: does not need any communication channel behind the membrane as it does not trigger anything inside the cell. Thus, ACE2 does not appear as a receptor leading to signaling, and tentatively I suggest that signaling might lie in the endocytosis of the receptor, in a broader sense of signaling (maybe earlier staged in evolution: no G-proteins, no cascade...) and in contrast to just blindly harbouring an enzmye on the membrane. Edited, see comments: it's not blindly that ACE2 has been "expressed", I realized that the very expression of proteins - be it on surface or not or not at all - can be seen as signaling.
Interestingly, especially Sars-Cov-2's spike is known to be cleaved by other enzymes on the cell's membrane (furine). Edited: Another exciting perspective: ACE2 which is a cleaving enzyme isn't used by the virus in its cleaving function, it looks like some exchange of "enzyme", not receptor. This is interesting in the context of CoV-2 mutations which add to specifity. Compare newer comment below: what normal interaction is "perturbed" by binding of CoV-2 to ACE2? My point is that there is no signaling cascade after ACE2 which could be perturbed - however, there is "competitive binding", as it is known with any other receptor, so a new way to look at CoV-ACE2 is to see a longer lasting state of blocking the receptor, shielding it away from its natural ligand (sorry, edited: such kind of poetrick is very familiar "competitive binding") Angiotensin II, and I couldn't tell if such kind of non use might trigger endocytosis, haven't heard of any "De-Overexpression", i.e. endocytosis of receptors that are not bound or used physiologically - which makes sense, as competive binding molecules are homologues, identical, how could one cell tell the difference? Aha, it's the "intrinsic effect" (you call it?) in contrast to just blocking - which in case of ACEII does not exist! Nothing behind ACE2 as some follow up cascade.) To me it's a possibility that the getting used of Furine triggers endocytosis of ACE2 (I don't think it does, End of editing).
That should bring up some other question - importance of receptor expression (that is discussed in the context of blood pressure medication, i.e. ACE antagonists as medication). Now, in context of this question, the expression as such just as the opposite, the endocytosis (which physiologically does not seem to be undertaken) might be seen as a way of regulation. So, why is ACE2 endocytosed, and why isn't it...
...however, it is also possible that SARS-CoV-2 can enter cells independently of ACE2 when viral loads are high.
This might be explained by SARS-CoV-2 not searching for a receptor that is endocytosed to facilitate entry by receptor-mediated endocytoses but attaches to any antigen that fits its spike, which speaks in favour of my assumption that it is the closeness of membranes. This is quite exciting as it's on the side of the victim - as I postulated - if ACE2 is prone or not to be endocytosed as the opposite of overexpression i.e. diminishing ACE2 is the way (to go away the way to go :-))
Edited, found https://pubmed.ncbi.nlm.nih.gov/15897343/ Confer at figure 4. Endocytosis of receptor not necessary(?)