New structure gives insight into mRNA export and cancers, and how viruses hijack the process to infect their host

The central dogma of biology defines the flow of genetic information: It describes how proteins are made from mRNA templates, which are in turn made from DNA. Exporting the mRNA from inside the nucleus to the site of protein translation in the cytoplasm is a critical step for life for eukaryotes like us.

Yi Ren's most recent paper, published in eLife, describes the structure of a protein complex involved in mRNA export that sheds light on the underlying molecular mechanism of mRNA export and the role it plays during infection by herpes viruses. Ren is an assistant professor in the Department of Biochemistry.

"Human cells carry tens of thousands of mRNAs. How does the cellular machinery handle such a diverse population of molecules and transport them from the nucleus where they are synthesized to the cytoplasm for protein translation?" she asked.

This is more than just an idle question. Understanding mRNA export is important not just for scientists to understand our cells' own functioning but is also critical from an infectious disease point of view. mRNA nuclear export is targeted by a variety of viruses to block host gene expression and immune response and/or promote viral gene expression. The Ren lab has previously shown that this is the case for the influenza A virus, the only known type of influenza that can cause flu pandemics, and SARS-CoV-2, the virus that causes COVID-19. Their latest research suggests that herpes viruses might also belong on that list.

The toll of these viral infections worldwide is almost unimaginable. Influenza alone causes about a billion cases worldwide each year. COVID-19 has caused, on average, almost 200 million cases annually since its emergence in 2020. And herpes simplex virus 1, which causes oral herpes and is incurable, affects nearly half of the world's population.

In the paper, first author Bradley Clarke and coauthors describe key steps in the mRNA nuclear export pathway and explain how the cellular machinery engages with newly synthesized mRNA.

mRNA has two ends, one of which is called the 5' end (pronounced "five prime") and which gets "capped" with a specially modified nucleotide before export. Clarke, a postdoctoral fellow and biochemistry alum, used cryo-electron microscopy to determine the structure for the nuclear cap binding complex and a key mRNA export factor, ALYREF.

The connection of CBC and ALYREF was reported almost two decades ago by Robin Reed's laboratory, but the underlying molecular basis was unknown.

"We couldn't have done it without the wonderful staff of the Cryo-EM Facility," Ren said. The Cryo-EM Facility, part of the Center for Structural Biology, aims to make transmission EM accessible to all Vanderbilt researchers.

The new CBC-ALYREF structure revealed molecular insights into the ALYREF-mediated recruitment of mRNA export machinery to the 5' end of nascent mRNA transcripts. The structure, along with biochemical results, also revealed the precise location of the CBC-ALYREF binding interface. Mutations in CBC at that interface, which the authors suggest could result in dysregulation of mRNA export, have been implicated in several forms of cancers.

The Ren lab also showed that herpes viruses-including KSHV, which causes Kaposi's sarcoma, and HSV-1, which primarily causes oral herpes-target that interface.

"Our work leads to a testable working hypothesis that herpes viruses may inhibit host mRNA export and thus host gene expression by interfering with the CBC-ALYREF interaction," Ren said.

Ren's lab is now working to understand how ALYREF coordinates the different steps in the mRNA nuclear export pathway and whether those steps are evolutionarily conserved.

A detailed mechanistic understanding of the mechanisms of action of ALYREF could pinpoint novel targets for potential anti-viral therapies and could deepen our understanding of the role of mRNA export and mRNA export dysfunctions in cancers.

Go deeper

The paper "Cryo-EM structure of the CBC-ALYREF complex " was published in eLife in September 2024.

Funding

This research used funds from the National Institutes of Health and the National Cancer Institute.

Shared resources

This research made use of the Cryo-EM Facility.

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