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bioRxiv · 10.1101/2025.09.10.675458

The Ubiquitin-Proteasome Pathway Mediates Selective Degradation of Unloaded Argonautes in C. elegans

Zhao, J. M.·Nguyen, D. A. H.·Cervantes, D.·Vong, B.·Phillips, C. M.
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Abstract

Argonaute proteins are essential effectors of small RNA-mediated gene regulation, yet the extent to which their stability depends on small RNA loading remains poorly understood. In Caenorhabditis elegans, we systematically disrupted the small RNA binding capacity of multiple Argonaute proteins to assess their stability in the absence of small RNA partners. We found that while most Argonautes remain stable when unable to bind small RNAs, a subset, including PRG-1, HRDE-1, and PPW-2, exhibited markedly reduced protein levels. Focusing on the Piwi-clade Argonaute PRG-1, we show that its destabilization occurs post-translationally and is independent of mRNA expression or translational efficiency. Instead, unbound PRG-1 is targeted for degradation by the ubiquitin-proteasome system. Additionally, the failure to load piRNAs disrupts PRG-1 localization to perinuclear germ granules. We further identify the E3 ubiquitin ligase EEL-1 as a factor promoting degradation of unloaded PRG-1. These findings uncover a critical role for small RNA loading in maintaining the stability and localization of a subset of Argonaute proteins, and reveal a quality control mechanism that selectively eliminates unbound PRG-1 to preserve germline regulatory fidelity.

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Zhao, J. M., Nguyen, D. A. H., Cervantes, D., Vong, B., Phillips, C. M.. 2025-09-12. The Ubiquitin-Proteasome Pathway Mediates Selective Degradation of Unloaded Argonautes in C. elegans. https://doi.org/10.1101/2025.09.10.675458

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