Loss of Drosophila nucleostemin 1 disrupts ribosomal protein homeostasis and rRNA processing to trigger apoptosis via the Xrp1/Irbp18 complex.

Abstract

Ribosome biogenesis, a process of producing ribosomes, plays an essential role in cell survival, proliferation and apoptosis. Nucleostemin (NS) is a conserved nucleolar protein highly expressed in proliferating cells but markedly reduced in differentiated cells. Previous studies on mammalian systems have shown that loss of NS triggers p53-dependent apoptosis and impairs ribosomal RNA (rRNA) processing. In this study, using the Drosophila wing imaginal disc, which is a proliferating epithelial tissue, we demonstrate that depletion of Ns1, the Drosophila homolog of mammalian NS, induces extensive p53-independent apoptosis and suppresses global translation. Notably, we find that Ns1 is required not only for rRNA processing but also for maintaining global ribosomal protein (RP) abundance. Loss of Ns1 leads to a reduction in 65 RPs. Furthermore, we show that Ns1 deficiency upregulates the Xrp1/Irbp18 complex, an effector mediating cellular response to ribosomal deficiency, which in turn activates JNK to trigger apoptosis and suppresses global translation through a mechanism independent of eIF2α phosphorylation and JNK. Our work establishes Ns1 as a critical regulator of ribosome biogenesis and cell survival in proliferating epithelia.