The La (SS-B) autoantigen, a key protein in RNA biogenesis, is dephosphorylated and cleaved early during apoptosis.
In the past few years, a role for apoptotic processes in the development of autoimmune diseases has been suggested. An increasing number of cellular proteins, which are modified during apoptosis, has been described, and many of these proteins have been identified as autoantigens. We have studied the effects of apoptosis on the La protein in more detail and for the first time demonstrate that this autoantigen is rapidly dephosphorylated after the induction of apoptosis. Dephosphorylation of the La protein was observed after induction of apoptosis by several initiators and in various cell types. Furthermore, we demonstrate that at least a subset of the La protein is proteolytically cleaved in vivo, generating a 45 kDa fragment. Dephosphorylation as well as cleavage of La is inhibited by ZnSO4 as well as by several tetrapeptide caspase inhibitors, indicating that these processes require the activation of caspases. Dephosphorylation of La is inhibited by low concentrations of okadaic acid, suggesting that a PP2A-like phosphatase is involved. Generation of the 45 kDa fragment is consistent with proteolytic cleavage at amino acids 371 and/or 374. The possible significance of the apoptotic changes in the La protein for autoantibody production is discussed.
Rutjes
S A
SA
Department of Biochemistry, University of Nijmegen, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands.
Utz
P J
PJ
van der Heijden
A
A
Broekhuis
C
C
van Venrooij
W J
WJ
Pruijn
G J
GJ
D000595:Amino Acid Sequence; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001324:Autoantigens / Q000187:drug effects / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D018929:Cell Culture Techniques; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008969:Molecular Sequence Data; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis*; D012261:Ribonucleoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays; D000097585:SS-B Antigen
D000841:Anisomycin; D000893:Anti-Inflammatory Agents; D001324:Autoantigens; D061945:Caspase Inhibitors; D020169:Caspases; D003609:Dactinomycin; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D019319:Okadaic Acid; D011500:Protein Synthesis Inhibitors; D012313:RNA; D012261:Ribonucleoproteins; D000097585:SS-B Antigen