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Paul J. Utz^*, Maria Hottelet^*, Walther J. van Venrooij, and Paul Anderson^*

From the ^* Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham & Women's Hospital, Boston, Massachusetts 02115; and the Department of Biochemistry, University of Nijmegen, 6500 HB Nijmegen, The Netherlands

Proteins subject to proteolysis or phosphorylation during apoptosis are commonly precipitated by autoantibodies found in the serum of patients with systemic lupus erythematosus (SLE). We screened a panel of murine monoclonal and human monospecific sera reactive with known autoantigens for their ability to selectively precipitate phosphoproteins from apoptotic Jurkat T cell lysates. Sera known to recognize the U1–small nuclear ribonucleoprotein (snRNP) complex (confirmed by their ability to precipitate U1–snRNA) selectively precipitated a phosphoprotein complex (pp54, pp42, pp34, and pp23) from apoptotic lysates. Monoclonal antibodies reactive with U1–snRNP proteins precipitated the same phosphoprotein complex from apoptotic lysates. The phosphorylation and/or recruitment of these proteins to the U1–snRNP complex is induced by multiple apoptotic stimuli (e.g., Fas ligation, gamma irradiation, or UV irradiation), and is blocked by overexpression of bcl-2. The U1–snRNP-associated phosphoprotein complex is immunoprecipitated by monoclonal antibodies reactive with serine/arginine (SR) proteins that comprise a structurally related family of splicing factors. The association of phosphorylated SR proteins with the U1–snRNP complex in cells undergoing apoptosis suggests a mechanism for regulation of alternative splicing of apoptotic effector molecules.

The authors thank J. Craft and members of the laboratories of P. Anderson, R. Reed, and M. Streuli for insights and helpful comments; Q. Medley and A. Da Silva for assisting with two-dimensional peptide mapping; V. Shifrin and Q. Medley for critical review of the manuscript; the Brigham & Women's Hospital Clinical Immunology Laboratory; P.H. Schur, P. Fraser, J. Craft, M. Kuwana, C. Casiano, E. Tan, E.A. Nigg, C. Zhang, D. Weaver, T. Medsger, N. Fertig, D. Bloch, A. Rosen, S. Hoch, N. Kedersha, R. Reed, K.M. Pollard, and M. Robertson for providing monoclonal and polyclonal antibodies used in this study; R. de Wildt and R.M.A. Hoet for providing the anti-U1A human variable chain antibody fragments; and J. Reed for the gift of the bcl-2– and neo-overexpressing Jurkat cells.

This work was supported in part by the Arthritis Foundation (P.J. Utz and P. Anderson); the National Institutes of Health grants AI33600 and CA67929 (P. Anderson); and the Peabody Foundation (P. Anderson). P. Anderson is a Scholar of the Leukemia Society of America. The work of W.J. van Venrooij was supported in part by the Netherlands Foundation for Chemical Research (SON) with financial aid from the Netherlands Organization for Scientific Research (NWO) and the Netherlands Technology Foundation (STW).

Address correspondence to Paul J. Utz, Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham & Women's Hospital, Smith Bldg., Rm. 608, 75 Francis St., Boston, MA 02115. Phone: 617-525-1216; Fax: 617-525-1310; E-mail: pjutz{at}rics.bwh.harvard.edu

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