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Chronic Fatigue Syndrome Research: G-Actin Cleavage Parallels 2-5A-Dependent RNase L Cleavage in Peripheral Blood Mononuclear Cells

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www.ProHealth.com • March 27, 2002




G-Actin Cleavage Parallels 2-5A-Dependent RNase L Cleavage in Peripheral Blood Mononuclear Cells - Relevance to a Possible Serum-Based Screening Test for Dysregulations in the 2-5A Pathway


Journal: J of Chronic Fatigue Syndrome, Vol. 8. No. 3/4. 2001. pp. 63-82


Authors: Simon Roelens, MS; C. Vincent Herst, PhD; Anne D'Haese, MS; Karen De Smet, PhD; Marc Frémont, PhD; Kenny De Meirleir, MD, PhD; Patrick Englebienne, PhD


Affiliations: Simon Roelens, C. Vincent Herst, Anne D'Haese, Karen De Smet and Marc Frémont are affiliated with RED Laboratories, N.V., Brussels, Belgium. Kenny De Meirleir is affiliated with the Vrije Universiteit Brussel, Brussels, Belgium. Patrick Englebienne is affiliated with the Université Libre de Bruxelles (Brugmann Hospital) and is Consultant, RED Laboratories, Brussels, Belgium.


Address correspondence to: Dr. Patrick Englehienne, RED Laboratories, N.V., Pontbeek 61, B-1731 Zellik, Belgium
(E-mail: mailto:penglebienne@redlabs.be ).


SUMMARY

A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L antiviral pathway has been detected in peripheral blood mononuclear cells (PBMC) of chronic fatigue syndrome (CFS) patients, which is characterized by an unregulated RNase L activity and the presence of a low molecular weight (LMW) 2-5A-binding protein (37-kDa 2-5A-BP).

This study was undertaken to test the possibility that the 37-kDa 2-5A-BP of CFS is produced by proteolytic cleavage of the 80-kDa monomeric enzyme.

Incubation of the 80-kDa human recombinant RNase L (r-hRNase L) with PBMC extracts either positive or negative for the presence of 37-kDa 2-5A-BP, respectively, demonstrates that the LMW protein is produced by the former, not the latter, and that the size of the fragment generated from the recombinant protein matches the 37-kDa size of the fragment observed in the original PBMC.

Digestion of r-hRNase L with calpain generated the same 37-kDa 2-5A-BP observed in PBMC extracts, and calpain immunoprecipitation from PBMC extracts reduced their proteolytic activity, an observation that suggests that calpain may be involved in the cleavage. We further examined G-actin, a known calpain substrate, for possible cleavage in PBMC. Actin fragments were observed of which the presence correlated with the presence of 37-kDa 2-5-BP. Since G-actin is cleared by serum transport, we further screened serum samples for the presence of LMW forms.

A single LMW actin fragment could be detected in serum, the presence of which correlated significantly with the presence of both G-actin and RNase L fragments in PBMC. This latter observation offers the opportunity to screen large populations of patients for dysregulations in the RNase L pathway by a serum-based assay.


KEYWORDS. G-Actin, RNase L, 37-kDa 2-5A-binding protein, chronic fatigue syndrome, CFS, serum screening test, apoptosis, PBMC, 2-5A pathway, calpain


INTRODUCTION

The interferon (IFN)-inducible 2',5'-oligoadenylate (2-5A) synthetase/ribonuclease L (RNase L) pathway is involved in eukaryotic cell protection against viruses. IFN triggers the production of nearly micromolar concentrations of 2-5A by virus-infected cells (1). The 2-5A are generated from ATP by any of several isozymes of an 2-5A synthetase specifically activated by double-stranded RNA of viral origin (2). The regulation by IFN of the 2-5A anti-viral mechanisms involves also the enhanced expression of an 2-5A-dependent RNase, termed RNase L. This 80 kDa monomeric latent protein is activated by binding 2-5A and homodimerizes during this activation process (3). The activated dimeric enzyme cleaves single-stranded RNA of viral and cellular origin, primarily after UpNp sequences (4), which results in the inhibition of protein synthesis.


Chronic fatigue syndrome (CFS) is a poorly understood physical condition defined exclusively by a group of symptoms listed in the case definition developed by the Centers for Disease Control and Prevention (reviewed in 5).

Typically, the onset of CFS is sudden, often with a flu-like illness, and an accumulating body of evidence suggests that CFS results from a dysregulation of both humoral (6) and cellular (7) immunity. Several causes have been suggested for the onset and maintenance of the disease, including the reactivation of hidden viral infections (8). However, subsequent studies demonstrated that this etiology could not be generalized (9). Recently, an increased sensitivity to glucocorticoids has been proposed as the origin for the altered immune function of CFS (10).


Early on, a severe dysregulation in the key components of the 2-5A pathway had been evidenced in CFS (11, 12) and more recently (13), a LMW 37-kDa 2-5A binding RNase L form (37-kDa 2-5A-BP) has been identified in the peripheral blood mononuclear cells (PBMC) of CFS patients. Further to this latter finding, the 37-kDa 2-5A-BP has been proposed as a possible biochemical marker for CFS (14). Whilst proteolytic degradation of the 80-kDa native enzyme has been suggested as a possible origin for the LMW form (13), no definitive evidence has so far been provided. Using a recombinant human RNase L (r-hRNase L), we show in this report that the LMW form present in CFS PBMC arises by proteolytic cleavage of the 80-kDa monomeric enzyme.

Moreover, we show that G-actin, a calpain substrate is also cleaved in CFS PBMC and the presence of actin fragments correlates with the presence of RNase L fragments. These data further support the involvement of an increased rate of immune cell apoptosis in the onset and maintenance of the disease (15).

Because G-actin is cleared from damaged cells by serum transport (16), we looked for the presence of fragments in serum and report here that the presence of a G-actin fragment in serum correlates significantly with the presence of both G-actin and RNase L fragments in PBMC. We finally suggest to use the detection of G-actin fragment in serum as a screening test for dysregulations in the 2-5A pathway, which would eventually be confirmed by the detection of the 37-kDa 2-5A-BP in PBMC (14).


[Article copies available for a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail address: mailto:getinfo@haworthpressinc.com Website: http://www.HaworthPress.com ]


(c) 2001 by The Haworth Press, Inc. All rights reserved.



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