DNA damage repair enzyme APE1 is a non-classical secretory protein and acts as a mediator of IL6 dependent inflammatory responses (IRM11P.626)

Apurinic/apyrimidinic endonuclease 1 (APE1) is a pleiotropic nuclear protein with roles in DNA base excision repair (BER) pathway as well as in transcriptional regulation. APE1 has been found to be systematically released in blood plasma during endotoxemia in rats. However, the physiological importance of this secretion remains elusive. Here, we show that both normal human monocytes and monocytic cell line THP-1 secrete APE1 upon inflammatory challenges. This secretion follows a non-classical route of transportation and requires ATP-binding cassette transporters. Challenging the THP-1 cells with purified recombinant APE1 (recAPE1) in culture media shows increased expression and secretion of pro-inflammatory cytokine IL6. Phosphorylation of transcription factor NFҡB-p65 upon recAPE1 treatment precedes increased occupancy to IL6 promoter resulting in induced expression of the cytokine. Extracellular IL6 further promotes the secretion of APE1 thus working in a positive feedback loop. Moreover, release of APE1 by necrotic cells indicates stress responsive behavior of this secretion. Together, our study demonstrates a novel role of extracellular APE1 and identifies secretory APE1 as a mediator of IL6 dependent inflammatory responses.