SGM Journals

Research explained · Herpesvirus and cell death

How does HSV-2 R1 interrupt a cell’s self-destruct signal?

The full-length HSV-2 R1 protein blocked activation of caspase-8, an enzyme involved in programmed cell death, in lab-grown cells exposed to two signals at receptors on the cell surface. Cells could still die when several other signals acted through mitochondria. That comparison located the block at or before caspase-8 activation in the receptor pathway. [1]

See original studies View the SGM research record

Two routes to cell death behaved differently

Signals from death receptors
The team activated death-receptor pathways using two signaling proteins, TNF and Fas ligand.
HSV-2 R1 prevented the resulting caspase-8 activation in the cells studied. [1]
Signals through mitochondria
Several other triggers, including making cells produce extra Bax protein, initiated programmed cell death through mitochondria.
Those stimuli still killed cells in the presence of R1 under the study conditions. [1]
The R1 protein in pieces
The researchers also tested the N-terminal region, the part of R1 at the beginning of its amino-acid chain.
That region offered no protection on its own in the assay. [1]

What is the advantage of testing two routes?

The cells could still die when the researchers used triggers that act through mitochondria. R1’s effect in these assays therefore lay in the tested receptor pathway, at caspase-8 activation or at an earlier step. [1]

What did a later experiment add?

Later cell experiments found that R1 from either HSV-1 or HSV-2 could interact with caspase-8. That interaction offers one explanation for the block reported in 2002. [1][2]

How broad is the result?

The researchers studied selected signals in lab-grown cells. How much the mechanism contributes in a particular tissue or stage of natural infection remained outside the experiment. [1][2]

Original research

  1. Langelier et al. (2002), Journal of General Virology. The R1 subunit of herpes simplex virus ribonucleotide reductase protects cells against apoptosis at, or upstream of, caspase-8 activation. Primary comparison of death-receptor and mitochondrial triggers.
  2. Dufour et al. (2011), Apoptosis. The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8. Follow-up cell experiments on the R1–caspase-8 interaction.