- •Small cell lung cancer (SCLC) neuronal autoantigen ELAVL4 becomes isoaspartylated in vitro.
- •ELAVL4 becomes isoaspartylated in vivo, in mice deficient in the isoaspartyl repair enzyme, PIMT.
- •Tumors from SCLC patients show reactivity with a new isoaspartyl-ELAVL4 rabbit antiserum we raised.
- •Isoaspartylated ELAVL4 is highly immunogenic in mice and human peripheral blood monocytic cells.
- •Anti-ELAVL4 positive SCLC patient antisera react with the isoaspartyl-prone ELAVL4 N-terminus.
Autoantibodies against SCLC-associated neuronal antigen ELAVL4 (HuD) have been linked to smaller tumors and improved survival, but the antigenic epitope and mechanism of autoimmunity have never been solved. We report that recombinant human ELAVL4 protein incubated under physiological conditions acquires isoaspartylation, a type of immunogenic protein damage. Specifically, the N-terminal region of ELAVL4, previously implicated in SCLC-associated autoimmunity, undergoes isoaspartylation in vitro, is recognized by sera from anti-ELAVL4 positive SCLC patients and is highly immunogenic in subcutaneously injected mice and in vitro stimulated human lymphocytes. Our data suggest that isoaspartylated ELAVL4 is the trigger for the SCLC-associated anti-ELAVL4 autoimmune response.
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- Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy.Autoimmun. Rev. 2009; 8: 410-414
- The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy.Clin. Immunol. Immunopathol. 1996; 78: 120-129
- Absence of HuD gene mutations in paraneoplastic small cell lung cancer tissue.Neurology. 1998; 50: 1919
- Molecular analysis of the HuD gene in neuroendocrine lung cancers.Lung Cancer. 2010; 67: 69-75
- Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer—a quantitative Western blot analysis.Ann. Neurol. 1990; 27: 544-552
- Anti-Hu—associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients.Medicine (Baltimore). 1992; 71: 59-72
- Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies.Lancet. 1993; 341: 21-22
- Damaged proteins bearing L-isoaspartyl residues and aging: a dynamic equilibrium between generation of isomerized forms and repair by PIMT.Curr. Aging Sci. 2011; 4: 8-18
- Regional and subcellular distribution of protein carboxymethylase in brain and other tissues.J. Neurochem. 1976; 26: 1159-1165
- High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types.Ann. Clin. Transl. Neurol. 2014; 1: 822-832
- A failure to repair self-proteins leads to T cell hyperproliferation and autoantibody production.J. Immunol. 2003; 171: 2840-2847
- Isoaspartyl post-translational modification triggers anti-tumor T and B lymphocyte immunity.J. Biol. Chem. 2006; 281: 32676-32683
- Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival.J. Clin. Oncol. 1997; 15: 2866-2872
- Selection of recombinant anti-HuD Fab fragments from a phage display antibody library of a lung cancer patient with paraneoplastic encephalomyelitis.J. Neuroimmunol. 1998; 82: 200-209
- Crystal structure of a protein repair methyltransferase from Pyrococcus furiosus with its l-isoaspartyl peptide substrate.J. Mol. Biol. 2001; 313: 1103-1116
- Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.J. Neurol. Neurosurg. Psychiatry. 2009; 80: 412-416
- SEER Cancer Statistics Review, 1975–2011.National Cancer Institute, Bethesda, MD2013 (http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014)
- Formation of isoaspartate at two distinct sites during in vitro aging of human growth hormone.J. Biol. Chem. 1989; 264: 14262-14271
- Chemotherapy for small-cell lung cancer.Lancet Oncol. 2014; 15: 13-14
- Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy.Mol. Cancer. 2011; 10: 33
- Immune response in lung cancer mouse model mimics human anti-Hu reactivity.J. Neuroimmunol. 2009; 217: 38-45
- Protein isoaspartate methyltransferase is a multicopy suppressor of protein aggregation in Escherichia coli.J. Bacteriol. 2005; 187: 1377-1383
- Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice.Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6132-6137
- Long-term survival of a patient with small cell lung cancer associated with cancer-associated retinopathy.Lung Cancer. 2007; 57: 399-403
- Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes.Immunol. Rev. 1998; 164: 231-239
- Isoaspartyl post-translational modification triggers autoimmune responses to self-proteins.J. Biol. Chem. 1999; 274: 22321-22327
- Hu antigens: reactivity with Hu antibodies, tumor expression, and major immunogenic sites.Ann. Neurol. 1995; 38: 102-110
- Tissue-specific expression of isoaspartyl protein carboxyl methyltransferase gene in rat brain and testis.J. Neurochem. 1994; 62: 322-328
- Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer.J. Clin. Oncol. 2004; 22: 795-800
- DNA vaccination against HuD antigen elicits antitumor activity in a small-cell lung cancer murine model.Am. J. Respir. Cell Mol. Biol. 1999; 21: 37-43
- Spontaneous alterations in the covalent structure of synapsin I during in vitro aging.Biochem. Biophys. Res. Commun. 1995; 212: 442-448
- Neuronal ELAVL Proteins Are Prone to Isoaspartylation.2016 (Manuscript submitted to Data in Brief)
- Isoaspartyl protein damage and repair in mouse retina.Invest. Ophthalmol. Vis. Sci. 2014; 55: 1572-1579
- Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines.Cancer Res. 1994; 54: 4988-4992
- Isoaspartate formation and neurodegeneration in Alzheimer's disease.Arch. Biochem. Biophys. 2000; 381: 225-234
- The HuD paraneoplastic protein shares immunogenic regions between PEM/PSN patients and several strains and species of experimental animals.J. Neuroimmunol. 1996; 71: 199-206
- Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice.Neurology. 1995; 45: 1873-1878
- Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome.J. Neurol. Neurosurg. Psychiatry. 1999; 66: 97-99
- CDR2 antigen and Yo antibodies.Cancer Immunol. Immunother. 2011; 60: 283-289
- Antibodies against autologous tumor cell proteins in patients with small-cell lung cancer: association with improved survival.J. Natl. Cancer Inst. 1993; 85: 2012-2018
- Deficiency in protein l-isoaspartyl methyltransferase results in a fatal progressive epilepsy.J. Neurosci. 1998; 18: 2063-2074
- Intracellular protein modification associated with altered T cell functions in autoimmunity.J. Immunol. 2006; 177: 4541-4549
- Protein repair in the brain, proteomic analysis of endogenous substrates for protein l-isoaspartyl methyltransferase in mouse brain.J. Biol. Chem. 2006; 281: 33802-33813
- Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging.J. Biol. Chem. 2006; 281: 2151-2161
Published online: September 02, 2016
Accepted: September 2, 2016
Received in revised form: August 31, 2016
Received: May 9, 2016
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