Fusion at the Surface or Inside the Endosome | Visual AI Learning Guide

Watch the two routes side by side. On the left, the virion binds its receptor at the plasma membrane and the fusion protein fires immediately, merging the viral envelope with the cell surface; the capsid enters directly. On the right, the virion is first taken up into an endosome. As the endosome matures, its lumen acidifies, and only then does the fusion protein fire, merging the viral envelope with the endosomal membrane. The trigger is the deciding factor: low pH, proteolytic cleavage, or both. A cell that supplies the activating protease at the surface allows the direct route; a cell that does not may still allow entry through the endosome, where acidification supplies the trigger. Notice that the capsid always ends up in the cytosol — only the membrane it crosses differs.

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An enveloped virion carries a lipid bilayer studded with a fusion protein, and entry means merging that bilayer with a host membrane so the capsid reaches the cytosol. Two routes achieve this. In fusion at the plasma membrane, the fusion protein is triggered directly at the cell surface, and the viral envelope merges with the plasma membrane. In endosomal entry, the virion is first taken up by endocytosis; the fusion protein is then triggered inside the endosome, and the viral envelope merges with the endosomal membrane, releasing the capsid into the cytosol.

The trigger is what distinguishes the routes. Fusion proteins are metastable: they are held in a high-energy, primed conformation and spring into a lower-energy, fusogenic form only when a specific trigger arrives. Two triggers recur. Low pH, generated as the endosome matures and its lumen is acidified, activates fusion proteins that are built to fire in the endosome. Proteolytic cleavage by a host protease — for example furin in the secretory pathway, or a surface protease such as TMPRSS2 — primes the fusion protein by cutting it into a receptor-binding subunit and a fusion subunit; without that cut the protein cannot refold into the fusogenic state. Some viruses require both: cleavage primes the protein, and low pH supplies the final trigger.

This is why the same virus can use different routes in different cells. A cell that expresses the activating protease at the surface permits plasma-membrane fusion; a cell that lacks it may still take the virion in by endocytosis, where the acidic lumen supplies the trigger. The route is therefore not fixed by the virus alone but by the combination of receptor, protease, and pH environment the virion encounters.