Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection

Abstract

Summary: Plasmodium parasites are highly selective when infecting hepatocytes and induce many changes within the host cell upon infection. While several host cell factors have been identified that are important for liver infection, our understanding of what facilitates the maintenance of infection remains incomplete. Here, we describe a role for phosphorylated ribosomal protein S6 (Ser235/236) (p-RPS6) in Plasmodium yoelii-infected hepatocytes. Blocking RPS6 phosphorylation prior to infection decreases the number of liver stage parasites within 24 h. Infected hepatocytes exhibit elevated levels of p-RPS6 while simultaneously abrogating the induction of phosphorylation of RPS6 in response to insulin stimulation. This is in contrast with the regulation of p-RPS6 by Toxoplasma gondii, which elevates levels of p-RPS6 after infection but does not alter the response to insulin. Our data support a model in which RPS6 phosphorylation is uncoupled from canonical regulators in Plasmodium-infected hepatocytes and is relied on by the parasite to maintain infection. : After mosquito-to-human transmission, Plasmodium parasites infect hepatocytes. Glennon et al. demonstrate that infected cells exhibit elevated levels of ribosomal protein S6 phosphorylation, and this phosphorylation appears uncoupled from canonical regulators. This work raises the possibility that Plasmodium-infected hepatocytes are governed by non-canonical, re-wired signal transduction cascades. Keywords: hepatocyte, Plasmodium, ribosomal protein S6, Toxoplasma, signal transduction