Pandey, M., Bajaj, G. D. and P. Rath. 2004. Induction of the interferon-inducible RNA-degrading enzyme, RNase L, by stress inducing agents in the human cervical carcinoma cells. RNA Biology 1 (1) 21-27.
This is yet another paper on the basic functioning of RNase L that may have real implications for CFS patients. Despite much research into RNase L over the last decade it is still unclear which agents – other than viral dsRNA – activate it. In order to begin to rectify that situation this study bombarded cells not with viral or microbial agents but with cellular stress inducing agents (dsRNA (poly C), chemotherapeutic drugs, hydrogen peroxide, calcium chloride, TNF-a) and then checked to see if RNase L responded to these insults. (Poly C mimics virally produced dsRNA, cycloheximide is an antibiotic used to inhibit protein synthesis, calcium chloride produces membrane and osmotic stress, hydrogen peroxide produces oxidative stress, the chemotherapeutic drugs interfere with DNA replication).
RNase L is known to engage in the apoptotic process. Just when and where RNase L is activated during the apoptotic process is, I think, unclear. It is possible, for instance, that RNase L, mostly known as an antiviral enzyme, could engage in apoptosis initiated by pathogens and not by toxins. By bombarding cells with stress inducing agents these researchers were apparently trying to determine if RNase L activated by these agents as well.
Not only did rates of RNase L activity increase in response to all of these stress inducing agents but so did other indirect measures of RNase L activity (cellular RNA degradation, chromatin degradation, apoptosis).
Interestingly RNase L responded to two agents, hydrogen peroxide and calcium chloride, that may be increased in people with CFS given evidence of increased oxidative stress. While it is not clear that oxidative stress can deregulate RNase L (i.e. fragment it), this paper indicates oxidative stress could exacerbate the effects of RNase L deregulation. Indeed, levels of oxidative stress were shown to be positively correlated with symptom expression in CFS ABA.
Another stimulating finding was the vigorous response RNase L had to calcium chloride. Increased levels of cytosolic calcium activate several proteins involved in apoptosis, one of which (calpain) may fragment RNase L. Calcium chloride administration presumably (?) results in the increased levels of intracellular calcium. One wonders, given a possible (calcium) channelopathy caused by the release of ankyrin fragments during RNase L fragmentation, if RNase L fragmentation feeds on itself by causing increased levels of cellular calcium – which in turn increase rates of RNase L activity (fragmentation?) and cellular dysfunction.
The pattern of apoptosis in CFS patients is unusual; rates of apoptosis are increased at first and then – as the degree of RNase L fragmentation increases – they dramatically decline. It is this decline in apoptotic activity that suggests to De. Meirleir et. al. that the sicker CFS patients have difficulty eliminating virally infected or otherwise damaged cells from their system. These cells presumably exist in a kind of strange limbo – they are beaten up, possibly viral ridden cells that are probably near death, but linger on propagating mischief in the body. The possible tie-in here is the finding that cellular stress can activate the RNase L system during the apoptotic process.
Most startlingly, only the monomeric form of RNase L was detected in this study. Since only the monomeric form of RNase L is susceptible to fragmentation this suggests that cellular stress may be a key agent of RNase L fragmentation. In CFS ABA De Meirleir et. al. in fact suggest cellular stress is one of several risk factors for CFS. Unfortunately, the authors here state they believe the dominance of the monomeric form of RNase L was due to nothing more than the way the test was condtucted…..
In short, cellular stress – which the cells of CFS patients probably regularly encounter – activates RNase L. The two cellular stress inducing agents RNase L responded most vigorously to – hydrogen peroxide, calcium (chloride) – may be increased in CFS patients.