TDP ‐43 Mediates Autophagic Degradation of Yki by Stabilizing Ref(2)P in Drosophila

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The transcriptional co-activator Yki, the central effector of the Hippo signaling pathway, plays essential roles in regulating tissue growth, regeneration, and tumorigenesis. Although upstream signaling mechanisms controlling Yki activity have been extensively characterized, the molecular mechanisms that govern Yki protein homeostasis remain incompletely understood. In this study, we identify TAR DNA-binding protein 43 (TDP-43) as a critical regulator of Yki proteostasis and demonstrate that stabilization of the autophagic receptor Ref(2)P is indispensable for TDP-43-mediated Yki turnover. Our findings reveal that TDP-43 elevates Ref(2)P levels through two distinct mechanisms. At the post-translational level in the cytoplasm, TDP-43 disrupts the interaction between Ref(2)P and the kinase Dco, thereby preventing phosphorylation-dependent proteasomal degradation of Ref(2)P. At the post-transcriptional level in the nucleus, TDP-43 promotes Ref(2)P mRNA stability by interacting with the nuclear m6A reader protein Ythdc1, which facilitates recognition of N6-methyladenosine (m6A)-modified Ref(2)P transcripts and protects them from decay. Together, these findings delineate a dual regulatory mechanism by which TDP-43 controls Ref(2)P abundance and Yki proteostasis, providing new insights into the fine-tuning of Hippo pathway activity.

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