<i>C. elegans</i> E3 ubiquitin ligase EBAX-1 promotes non-apoptotic linker cell-type death through target-directed miRNA degradation

Programmed cell death is essential for animal development and homeostasis, and its disruption accompanies many human disorders. Linker cell-type death (LCD) is a morphologically conserved non-apoptotic developmental cell death program with features resembling polyglutamine-dependent neurodegeneration. In <i>C. elegans</i>, LCD execution is mediated by ubiquitin proteasome system (UPS) components, but their proteolytic targets are unknown. Here we demonstrate that EBAX-1/ZSWIM8, a conserved E3 ligase, promotes <i>C. elegans</i> LCD by target directed miRNA degradation (TDMD). We show that EBAX-1 acts cell-autonomously as part of the UPS and requires its Cullin-2 binding motif to promote LCD. Loss of <i>mir-35</i> family miRNAs, argonautes, or miRNA biogenesis factors, restores LCD to <i>ebax-1</i> mutants. Furthermore, expression of <i>viln-1</i>/villin mRNA, a predicted <i>mir-35</i> target, is upregulated in dying cells and is required for LCD. Together, our studies suggest that TDMD mediated by EBAX-1 is important for the fidelity of non-apoptotic developmental cell death.