Authors
Lu, K.-H., Yu, B.-H., Sang, T.-K.
Abstract
Cellular homeostasis relies on complex mechanisms that sense and respond to genotoxic stress. While autophagy adaptors are well-known for their role in removing cytoplasmic protein aggregates, their involvement in DNA damage responses is less clear. In this study, we show that Blue cheese (BCHS), the Drosophila homolog of mammalian Alfy/WDFY3, functions as a critical regulator connecting autophagy, DNA repair, and intercellular communication. Using a Drosophila eye model with TER94 (VCP ortholog) deficiency, we observed that genotoxic stress specifically increases expression and nuclear buildup of ref(2)P (p62/SQSTM1 homolog). Reducing BCHS worsens nuclear ref(2)P accumulation and DNA damage, while increasing BCHS levels alleviates these effects, highlighting BCHS as a vital regulator of nuclear proteostasis and genome stability. Mechanistically, genotoxic stress triggers reversible separation of the ref(2)P-BCHS complex, temporally coordinated with ref(2)P nuclear translocation. Strikingly, BCHS undergoes dynamic redistribution from the nuclear periphery to the extracellular matrix (ECM) via an exosome-dependent pathway involving Rab11, Rab27, Rab35, VAMP7, and tetraspanin Tsp96F. Blocking BCHS secretion significantly hampers DNA repair, demonstrating that extracellular BCHS export is functionally required for genome maintenance. These findings establish a paradigm wherein autophagy adaptors serve dual roles by coordinating nuclear stress responses while communicating cellular damage status to the tissue microenvironment. Given the conservation between BCHS and human Alfy, this mechanism may have broad implications for diseases characterized by defective proteostasis and genome instability, including neurodegeneration and cancer.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Nov 2025.
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