IL-17 promotes melanoma through TRAF2 as a scaffold protein recruiting PIAS2 and ELAVL1 to induce EPHA5

Junfeng Du; Yujia Du; Lang Chen; Hongwei Liu

doi:10.1016/j.bbamcr.2023.119547

IL-17 promotes melanoma through TRAF2 as a scaffold protein recruiting PIAS2 and ELAVL1 to induce EPHA5

Biochim Biophys Acta Mol Cell Res. 2023 Oct;1870(7):119547. doi: 10.1016/j.bbamcr.2023.119547. Epub 2023 Jul 21.

Authors

Junfeng Du¹, Yujia Du², Lang Chen³, Hongwei Liu⁴

Affiliations

¹ Department of Plastic Surgery, the first affiliated hospital of Jinan University, No. 613, Huangpu Avenue West, Tianhe District, Guangzhou 510630, China.
² Medical college of Jianghan University, No. 8, Sanjiaohu Road, Wuhan Economic and Technological Development Zone, Wuhan 430014, China.
³ Department of Burns and Plastic, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
⁴ Department of Plastic Surgery, the first affiliated hospital of Jinan University, No. 613, Huangpu Avenue West, Tianhe District, Guangzhou 510630, China; Innovative Technology Research Institute of Plastic Surgery, Guangzhou 510630, People's Republic of China; Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou 510632, People's Republic of China. Electronic address: hongweiliu86@163.com.

PMID: 37481078
DOI: 10.1016/j.bbamcr.2023.119547

Abstract

An abnormal immune response induces melanoma development. IL-17 and the classical downstream signal STAT1 are associated with melanoma development. TRAF2 also mediates the downstream signaling of IL-17; however, its role in IL-17-stimulated melanoma remains unclear. Bioinformatic analysis revealed that TRAF2 can bind to PIAS2 (a SUMO E3 ligase), ELAVL1 (an RNA-binding protein), and EPHA5 (an ephrin receptor of the tyrosine kinase family). To elucidate the IL-17 downstream signal, the IL-17 receptor (R), STAT1, TRAF2, PIAS2, ELAVL1, and EPHA5 were knocked down before melanoma cells were treated with recombinant IL-17A protein. Co-immunoprecipitation and RNA immunoprecipitation were conducted to determine the interaction of TRAF2 with PIAS2, ELAVL1, and EPHA5 proteins, as well as the interaction of ELAVL1 protein with EPHA5 mRNA. STAT1 knockdown suppressed the proliferation and invasion triggered by IL-17A, but the suppressive effects were much weaker than those caused by IL-17R knockdown. This implies that another nonclassical signal mediates IL-17 effects. IL-17A induces TRAF2 recruitment of ELAVL1, PIAS2, and EPHA5 proteins. We speculated that ELAVL1 bound to the AU-rich elements in the 3' untranslated region of the EPHA5 mRNA, thereby enhancing mRNA stability. Furthermore, PIAS2 induced EPHA5 SUMOylation, which suppressed EPHA5 ubiquitination and degradation. Through pre- and post-translational regulation, IL-17A induced EPHA5 expression in melanoma, and EPHA5 knockdown markedly suppressed IL-17A-induced proliferation and invasion. This study revealed a non-classical signaling mechanism responsible for the effects of IL-17 in melanoma.

Keywords: ELAVL1; EPHA5; IL-17; Melanoma; PIAS2; SUMOylation.