LINE1-ORF0 in SLE pathogenesis

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PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by sustained interferon (IFN) signaling and high titer autoantibodies leading to immune-mediated tissue damage. An abnormal accumulation of nucleic acids derived from retrotransposons, a class of transposable element, has been linked to diseases characterized by sustained IFN-I production, such as SLE. In particular, retrotransposons of the non- LTR LINE1 (L1) family have been shown to be activated in patients with SLE. More recently, it was found that the RNA-binding protein (ORF1p) and the ORF2p endonuclease/reverse transcriptase encoded by L1s are SLE autoantigens, supporting the notion that L1 elements may play a role in SLE pathogenesis. This proposal is focused on the study of a recently discovered antisense open reading frame (ORF) found in the L1 5’UTR, termed ORF0. ORF0 encodes for a small nuclear protein (ORF0p) of 71 amino acid residues, which increases L1 mobility. ORF0 has several unique features, which may have critical implications on the potential mechanistic role of L1s in SLE pathogenesis. First, the number of ORF0 loci capable of encoding full-length ORF0p (~781 loci) is ~8-10 times higher than ORF1 and ORF2 (~80–100 active copies). Thus, in the setting of L1 activation, such as in SLE, it is expected that the antigenic load of ORF0p would be more robust than ORF1p and ORF2p. Second, ORF0 has two prominent splice donor sites that act in concert with splice acceptors in downstream genomic sequences, generating ORF0p-fusion proteins. This is, the N-terminus of the “host” protein would be replaced by the ORF0p N-terminal sequence, producing hybrid proteins. Based on this premise, our central hypothesis is that L1 activation in SLE leads to ORF0 dysregulation, which drives the production of anti-ORF0p antibodies and an abnormal expression of hybrid ORF0p-fusion proteins, generating neoantigens targeted in SLE. Indeed, our preliminary studies demonstrate that ORF0p is an autoantigen in SLE. The major goal of this exploratory/developmental research grant is to investigate the clinical significance of anti-ORF0p antibodies in SLE and to address the hypothesis that patients with SLE have an abnormal production of ORF0p-host fusion proteins containing lupus autoantigens.