Paramyxovirus P gene expression

ryan at mbcf.stjude.org ryan at mbcf.stjude.org
Fri Jun 16 10:41:42 EST 1995


In article <1995Jun13.143618.49406 at ucl.ac.uk>, Naveed Panjwani <n.panjwani at lshtm.ac.uk> writes:
> I was reading about parainfluenza virus (The Biology of Parainfluenza
> viruses, Clin. Microbiol. Rev., 1994, 7(2)), and one aspect of it's
> molecular biology left me confused. I wonder if someone can sort it
> out...

Hi Naveed,
the picture isn't quite as complicated as your description suggests. Let's
take it point by point...
> 
> The P gene is multicistronic. Paramyxoviruses can be divided into 2
> groups based on how the P gene is expressed. PIV1 and PIV3 express the
> 500-600 aa product from continuous open reading frames in the P 
> gene transcript. Then another protein - C - is expressed from a discrete
> frame within the multicistronic transcript. 

All viruses in this group express a P protein, as it's needed for viral RNA
synthesis and nucleocapsid assembly. P translation is read from the longest
ORF in the P mRNA, with or without modification by nontemplated Gs.  

> 
> PIV2 & 4 have a different gene expression pattern. Here more than one
> species of transcript (mRNA) is generated by non-template dependent
> insertion of two G nucleotides at a specific point in the P gene.
> You therefore now have two possible P protein, and I find it impossible
> to see how an activity such as that which is ascribed to P protein can
> be preserved despite this kind of frameshift....

Not all P gene mRNAs have the nontemplated residues added; i.e. some mRNA
remains a true reverse-complementary copy of the sequences in the virus
genome; some transcripts get modified, allowing translation to access
information in an alternative reading frame. Proteins from both mRNAs are made.

>  
> ALSO...
> In the PIV2/4 expression strategy, a V protein is expressed from 
> the P gene, but directly from the positive sense genome and not from 
> transcribed -ve sense mRNA. Now, is this to say that in the other
> members of the family have the C protein expressed, and these 2 types 
> and their related animal viruses have the V protein expressed.
> This is inconsistent with the fact that the C protein has a highly 
> conserved cys-rich region that appears to a nucleic acid binding 
> domain. How can one group express a different protein that completely
> lacks an activity that seems so crucial..

A few points: as far as we know, no mRNA transcripts are copied from the (+)
sense copies of the virus genome RNA. These full-length reverse-complement
copies of the virus genome are replicative intermediates only, serving as
templates for the synthesis of new (-) sense virus genome molecules. All virus
mRNA is (+) sense by definition, just like yours and mine. These (+) sense
transcripts are copied from the (-) sense template [i.e. the virus genome]. V
protein contains the cys-rich domain.

To summarize: a typical parinfluenza virus makes an unmodified mRNA, which
produces translation products P, C, C'. Synthesis of these proteins is due to
multiple AUG initiation codons in this mRNA, with no AUG in a perfect context
for highly efficient translation (so some translation starts at each of the
three AUGs). P is encoded from one reading frame, C and C' from a different 
reading frame. (Not all paramyxoviruses make C and C'). The population of mRNA
that is modified by the addition of nontemplated nucleotides is translated as V
protein. Bases on the 5' side of the nontemplated nucleotides encode amino
acids identical to the amino end of P protein; bases in the modified mRNA on
the 3' side of the nontemplated nucleotides are in a new reading frame and
encode the cys-rich region. Think of V as a fusion protein (_not_ a
membrane-fusing protein) composed of the amino end of P and the cys-rich 
region stuck on as a carboxyl end.
In short, some viruses make P & V. Some make P & V & C & C'. In no case does a
virus lose the ability to make P during infection. Some mRNA molecules lose
that ability, some don't. This multi-cistronic strategy adds information to the
mRNA pool, but it doesn't remove any information.

Try to find a review of these topics by Lamb & Patterson in _The
Paramyxoviruses_ (Plenum, 1991). These people were first to report the addition
of nontemplated G residues to viral mRNA. The field has progressed since this
was published, so the information won't be quite as up to date as in the
reference you have, but it presents a good clear discussion of expression 
strategies.

Kevin.
-- 
--
       	==========================================
	Kevin W. Ryan
	Department of Virology & Molecular Biology
	St. Jude Children's Research Hospital
	Memphis, Tennessee 38101-0318, U.S.A.
	
	phone: (901) 522-0411
	fax:   (901) 523-2622
	Internet: ryan at mbcf.stjude.org
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