Highlights
- •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.
Abstract
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 02, 2016
Accepted:
September 2,
2016
Received in revised form:
August 31,
2016
Received:
May 9,
2016
Identification
Copyright
© 2016 Elsevier B.V. All rights reserved.
