RPLP1, a Crucial Ribosomal Protein for Embryonic Development of the Nervous System

Abstract

Ribosomal proteins are pivotal to development and tissue homeostasis. RP Large P1 (Rplp1) overexpression is associated with tumorigenesis. However, the physiological function of Rplp1 in mammalian development remains unknown. In this study, we disrupted Rplp1 in the mouse germline and central nervous system (Rplp1CNS Δ). Rplp1 heterozygosity caused body size reductions, male infertility, systemic abnormalities in various tissues and a high frequency of early postnatal death. Rplp1CNS Δ</emph> newborn mice exhibited perinatal lethality and brain atrophy with size reductions of the neocortex, midbrain and ganglionic eminence. The Rplp1 knockout neocortex exhibited progenitor cell proliferation arrest and apoptosis due to the dysregulation of key cell cycle and apoptosis regulators (cyclin A, cyclin E, p21CIP1, p27KIP1, p53). Similarly, Rplp1 deletion in pMEFs led to proliferation arrest and premature senescence. Importantly, Rplp1 deletion in primary mouse embryonic fibroblasts did not alter global protein synthesis, but did change the expression patterns of specific protein subsets involved in protein folding and the unfolded protein response, cell death, protein transport and signal transduction, among others. Altogether, we demonstrated that the translation “fine-tuning” exerted by Rplp1 is essential for embryonic and brain development and for proper cell proliferation.

RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation

“…It is not clear why RPLP1/2 knockdown causes different effects on cellular translation in these cell lines. However, these observations are in agreement with previous reports that showed variable effects on cellular translation upon RPLP1/2 depletion (30)(31)(32). Importantly, these data indicate that the potent reductions we observed in flavivirus infectivity upon RPLP1/2 knockdown cannot be explained by a generalized inhibition of cellular translation.…”

“…RPLP1/2 were also required for DENV-2 infection of A. aegypti mosquitoes, highlighting a conserved role for these host factors across different species. RPLP1/2 were not essential for protein synthesis in human cells, consistent with previous reports (30)(31)(32). Two lines of evidence implicate RPLP1/2 as drivers of flavivirus translation: (i) the early accumulation of DENV-2-expressed luciferase and NS3 was reduced in RPLP1/2 knockdown cells after infection, and (ii) RPLP1/2 depletion reduced expression levels of structural proteins in heterologous cell-based assays that bypass viral entry.…”

“…The stalk acts in recruitment of elongation factor eEF2, which functions in GTP-dependent ribosomal translocation (29). However, previous studies have reported little (ϳ20% reduction) to no change in global translation when RPLP1/2 are depleted in cells (30)(31)(32).Here, we show that RPLP1/2 are essential for DENV-2, YFV, and ZIKV infection. RPLP1/2 were also required for DENV-2 infection of Aedes aegypti mosquitoes, the main vector for these viruses.…”

“…The stalk acts in recruitment of elongation factor eEF2, which functions in GTP-dependent ribosomal translocation (29). However, previous studies have reported little (ϳ20% reduction) to no change in global translation when RPLP1/2 are depleted in cells (30)(31)(32).…”

Disruption of the ribosomal P complex leads to stress-induced autophagy

“…7 Moreover, similar results have been recently described by us in an in vivo knockout model of the RPLP1 protein where overall protein synthesis is not affected. 44 Overall, our data support the notion that RPLP proteins might have extraribosomal functions, which appear in stress-related conditions.…”