Sunday, July 10, 2011

Translation and protein processing by picornavirus

Translation and protein processing by picornavirus

The picornavirus RNA binds to ribosomes and makes a single polypeptide, therefore the virus has just one gene. This polyprotein has regions that have proteolytic activity (they are cysteine proteases) that cleave the polyprotein to three precursor proteins (P1, P2, P3). P1 is cleaved to a VP0, VP1 and Vp3 plus a leader peptide of unknown function. VP0 gives rise to VP2 and VP4. P2 and P3 do not give rise to viral structural proteins. One of the proteins that comes from P3 is the VPG that is found at the 5' end of the viral RNA while other proteins from this precursor are the viral replicase and enzymes that modify the behavior of the host cell. P2 is also cleaved to give other cell-modifying proteins. Details of some of the cleavages are still vague.

Once the various viral proteins have been made in the infected cell, the replicase (also call a transcriptase or protein 3Dpol) copies the viral plus sense RNA to negative sense RNA. Other viral proteins are also involved in this process. As new positive strand RNAs are made, they can also be translated into more viral protein. There may be as many as half a million copies of viral RNA per cell. Some of the proteolytic events outlined above take place as the nucleocapsid is assembled. This is especially the case with the VP0 cleavage to VP2 and VP4. P1 protein is the precursor that gives rise to the four structural proteins of the nucleocapsid. Five copies of P1 first associate. Endoproteolysis then occurs to form VP0, VP1 and VP3. Twelve of these pentamers than associate to form an empty capsid (procapsid). The viral RNA now associates with the capsid and at the same time, VP0 is cleaved. Release is by lysis of the host cell.

At the same time as viral protein synthesis is occurring, host cell protein synthesis is shut off. The host cell mRNAs however remain fully functional when assayed in an experimental system, so selective degradation of cell mRNAs is not the reason for protein synthesis inhibition. One way host cell protein synthesis occurs is via the cleavage of initiation factor eIF-4, one of the cap binding proteins of the host cell's ribosomes so that cellular mRNAs cannot bind to the ribosomes. Association with cap-binding proteins is a prerequisite for the translation of most cellular RNAs. Thus, only uncapped messages such as that of the picornavirus are translated. Note that most viruses express capped RNAs similar to normal mRNA and so this mechanism of shutting down host protein synthesis is not available to them. The viral proteins also change the permeability of the host cell, altering the ionic composition of the cell and inhibiting cell mRNA association with ribosomes. Moreover, the large number of copies of viral RNA simply out-compete the cell's mRNAs.

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