Structural Biochemistry/Short Linear Motifs and Viral Infection

Viruses and Cell Regulation

Viruses are known to be able to infect their host cells and even “hijack” them, taking control of normal cell metabolism and reproduction/replication. Viruses are able to change the host cell’s functionality by introducing their own DNA/RNA; as well as accompanying replication/transcription enzymes; such as DNA polymerase, and helicases. One way that the virus is able to take massive control of its host cell’s processes is through taking over the cell’s SLiM (short linear motifs). SLiMs are minimotifs that are existent in all eukaryotic cells/proteomes. SLiMs help regulate many of the cell’s processes, such as proteolytic cleavage, post-translational adjustments, and also aids in substituting as binding sites for cell signaling. They are also very unique in that they allow for encoding for very short translations for smaller proteins. With such diversity in functions of the cell, it has been argued that SLiMs are perhaps the most crucial element in the evolution of cells in the past and for the future. With such high evolutionary influence, SLiMs are also a very vulnerable as well as preferable portion of the cell for an invading virus to victimize in order to hijack the entire cell and its processes.

SLiM and Viral Plasticity

Due to the fact that SLiMs are very short in terms of length (only around 3-10 residues), as well as the variability in them, there is much room for evolutionary change, plasticity, and mutation. Upon mapping out an evolutionary history of known SLiMs, the only actual portion that remained conserved was the physicochemical properties. Most viruses are also known to have high mutation rates, which easily leads to convergent evolution; making viral motif mimicry relatively easy. Due to the high plasticity of most cellular motifs, the SLiMs are thought to be the weakest link for the cell in terms of vulnerability towards viruses.

Virus’ Influence on SLiM Transcriptional Regulation

A virus take-over of the SLiM can lead to severe effects on normal regulation of transcription. One example of a SLiM that controls transcriptional regulation would be the LxCxE motif, which binds to RB and controls the E2F transcription factor. Upon introducing a virus that would interfere with normal function of the LxCxE motif by forcing the cell to go (or stay) in S-phase. This stasis in the S-phase nullifies immune system response, and allows for more efficient virus proliferation. Other viruses such as HPV E7, a viral protein, invades the LxCxE motif by binding to RB pocket-binding domains, which overrides the cell’s usual regulatory checking system.

SLiMs and Cancer

Carcinogenesis has been known form as a secondary effect of viruses taking over the cell and SLiMs’ mechanics. Carcinogenesis is induced due to the deregulating effect that viruses have on cell’s cellular pathways; resulting in often irregular protein productions, in which the proteins/RNA responsible is ingrained into the replication process for the infected cell. The most notable viruses that cause carcinogenesis in cells would be human papillomavirus (HPV), hepatitis B/C, herpes (HHV), and HIV co-infections). These sexually transmitted viruses make up for about 12% of the developed cancer cases in humans. One example that correlates viral invasions to the creation of cancerous traits would be EBC LMP1, which forces proliferation and blocks the signals for natural cell apoptosis; two traits that are highly prominent in cancerous cells.

Other Methods of Viral Control of the Host

Although taking direct control of a cell’s motif system is a common and easy method for viruses to be able to thrive inside it’s host cell, it can take control by other means as well. One method is by indirectly influencing the motif control utilizing globular proteins and domains. Some examples of domains that do this are EBV BHRF-1, which binds specifically to BH3 motifs. Another example of this particular method would be STD viruses such as HIV or the bovine papillomavirus’ E6 oncoprotein. These particular viral proteins are able to bind onto paxillin, a cellular cytoskeletal protein.

Another mechanism of indirect motif control would be a viral infection leading to loss of the motif upon viral transferring into the host cell. The virus is able to do this by continually replicating itself and changing its genetic code via mutations until the sequence of the clone viral protein is virtually useless for the host cell. By becoming useless, the viral proteins are thus able to decouple from normal host cell regulation, allowing the virus to freely interact within the host cell. With massive mutations in the virus, the viral sequence cannot be identified by normal host cell enzymes such as FBW7 ubiquitin ligase adaptors.

References

http://www.sciencedirect.com/science/article/pii/S0968000410002008