The RNA interference pathway: a new target for autoimmunity

Many intracellular macromolecular complexes that are involved in the production or degradation of RNAs are targeted by autoantibodies in systemic autoimmune diseases. RNA interference (RNAi) is a recently characterized gene silencing pathway by which specific mRNAs are either degraded or translationally suppressed. In a recent issue of Arthritis Research and Therapy, Andrew Jakymiw and colleagues reported that the enigmatic Su autoantigen complex contains key components of the RNAi machinery. Anti-Su autoantibodies from both human patients with rheumatic diseases and a mouse model of autoimmunity recognize the endonucleolytic Argonaute and Dicer proteins, both crucial enzymes of the RNAi pathway. These data raise the question of how the anti-Su response is triggered. So far, it is unknown whether molecular modifications may be involved, as has been proposed for other intracellular autoantigens. The implication of RNAi in anti-viral defence may suggest a role for virus infection in this process

Density Fluctuations in an Electrolyte from Generalized Debye-Hueckel Theory

Near-critical thermodynamics in the hard-sphere (1,1) electrolyte is well described, at a classical level, by Debye-Hueckel (DH) theory with (+,-) ion pairing and dipolar-pair-ionic-fluid coupling. But DH-based theories do not address density fluctuations. Here density correlations are obtained by functional differentiation of DH theory generalized to {\it non}-uniform densities of various species. The correlation length $\xi$ diverges universally at low density $\rho$ as $(T\rho)^{-1/4}$ (correcting GMSA theory). When $\rho=\rho_c$ one has $\xi\approx\xi_0^+/t^{1/2}$ as $t\equiv(T-T_c)/T_c\to 0+$ where the amplitudes $\xi_0^+$ compare informatively with experimental data.Comment: 5 pages, REVTeX, 1 ps figure included with epsf. Minor changes, references added. Accepted for publication in Phys. Rev. Let

An important step towards completing the rheumatoid arthritis cycle

In the previous issue of Arthritis Research & Therapy data are presented showing that circulating immune complexes containing citrullinated fibrin(ogen) are present in anti-citrullinated protein antibody-positive rheumatoid arthritis patients, and that such immune complexes co-localize with complement factor C3 in the rheumatoid synovium. These results corroborate the idea that citrullination is intimately involved in the pathophysiology of rheumatoid arthritis and complete our model (the rheumatoid arthritis cycle) for the development and chronic nature of this disease

C1D and hMtr4p associate with the human exosome subunit PM/Scl-100 and are involved in pre-rRNA processing

The exosome is a complex of 3′–5′ exoribonucleases and RNA-binding proteins, which is involved in processing or degradation of different classes of RNA. Previously, the characterization of purified exosome complexes from yeast and human cells suggested that C1D and KIAA0052/hMtr4p are associated with the exosome and thus might regulate its functional activities. Subcellular localization experiments demonstrated that C1D and KIAA0052/hMtr4p co-localize with exosome subunit PM/Scl-100 in the nucleoli of HEp-2 cells. Additionally, the nucleolar accumulation of C1D appeared to be dependent on PM/Scl-100. Protein–protein interaction studies showed that C1D binds to PM/Scl-100, whereas KIAA0052/hMtr4p was found to interact with MPP6, a previously identified exosome-associated protein. Moreover, we demonstrate that C1D, MPP6 and PM/Scl-100 form a stable trimeric complex in vitro. Knock-down of C1D, MPP6 and KIAA0052/hMtr4p by RNAi resulted in the accumulation of 3′-extended 5.8S rRNA precursors, showing that these proteins are required for rRNA processing. Interestingly, C1D appeared to contain RNA-binding activity with a potential preference for structured RNAs. Taken together, our results are consistent with a role for the exosome-associated proteins C1D, MPP6 and KIAA052/hMtr4p in the recruitment of the exosome to pre-rRNA to mediate the 3′ end processing of the 5.8S rRNA

MPP6 is an exosome-associated RNA-binding protein involved in 5.8S rRNA maturation

The exosome is a complex of 3′→5′ exoribonucleases which is involved in many RNA metabolic processes. To regulate these functions distinct proteins are believed to recruit the exosome to specific substrate RNAs. Here, we demonstrate that M-phase phosphoprotein 6 (MPP6), a protein reported previously to co-purify with the TAP-tagged human exosome, accumulates in the nucleoli of HEp-2 cells and associates with a subset of nuclear exosomes as evidenced by co-immunoprecipitation and biochemical fractionation experiments. In agreement with its nucleolar accumulation, siRNA-mediated knock-down experiments revealed that MPP6 is involved in the generation of the 3′ end of the 5.8S rRNA. The accumulation of the same processing intermediates after reducing the levels of either MPP6 or exosome components strongly suggests that MPP6 is required for the recruitment of the exosome to the pre-rRNA. Interestingly, MPP6 appeared to display RNA-binding activity in vitro with a preference for pyrimidine-rich sequences, and to bind to the ITS2 element of pre-rRNAs. Our data indicate that MPP6 is a nucleolus-specific exosome co-factor required for its role in the maturation of 5.8S rRNA