Ubiquitination of LMP-1 by UFD-2 regulates apoptotic cell clearance

Apoptotic cell clearance, or efferocytosis, is essential for tissue homeostasis and preventing inflammation in multicellular organisms. Through a genome-wide RNAi screen targeting 169 E3 ubiquitin ligases in Caenorhabditis elegans, we identified six ligases involved in efferocytosis regulation, with UFD-2 deletion showing the most significant defect. UFD-2 was found to be critical for phagosome maturation and degradation during apoptotic cell clearance. We identified the lysosomal membrane protein LMP-1 as a direct substrate of UFD-2 and showed that UFD-2 cooperates with UBC-15 to catalyze K63-linked polyubiquitination of LMP-1, essential for efficient apoptotic cell clearance. Loss of UFD-2 resulted in reduced LMP-1 levels within lysosomes and impaired activation of lysosomal DNase NUC-1. The function of UFD-2 in efferocytosis is evolutionarily conserved, as its mammalian homolog UBE4B similarly regulates apoptotic cell clearance in macrophages. These findings establish UFD-2 as a key regulator of efferocytosis, providing therapeutic insights into diseases associated with defective efferocytosis.