Abstract

The c-Jun N-terminal kinase (JNK) pathway is an evolutionarily conserved signaling cascade that regulates development, stress responses, and pathogenesis. While aberrant JNK activation is linked to cancer and neurodegeneration, its regulatory mechanisms are not fully understood. Here, we identify the RNA-binding protein Ataxin-2 (Atx2) as a novel, essential regulator of JNK-mediated cell death and migration in Drosophila . Atx2 deficiency suppressed JNK-dependent apoptosis, tumor growth and invasion, and thorax closure in normal development, while its overexpression activated JNK signaling, promoting cell death, migration, and tissue remodeling. Mechanistically, Atx2 binds the 3′ UTR of hipk mRNA, stabilizing it to enhance the expression of Hipk, a core upstream JNK kinase. Strikingly, this mechanism is conserved: human ATXN2L potently activated Hipk-JNK signaling and cell death in Drosophila and HeLa cells. Our findings reveal a conserved post-transcriptional mechanism for JNK pathway regulation and nominate Atx2 family proteins as potential therapeutic targets in JNK-associated pathologies.