The Pallbearer E3 Ligase Promotes Actin Remodeling via RAC in Efferocytosis by Degrading the Ribosomal Protein S6

Abstract

Clearance of apoptotic cells (efferocytosis) is achieved through phagocytosis by professional or amateur phagocytes. It is critical for tissue homeostasis and remodeling in all animals. Failure in this process can contribute to the development of inflammatory autoimmune or neurodegenerative diseases. We previously found that the PALL-SCF E3-Ubiquitin ligase complex promotes apoptotic cell clearance, yet it remained unclear as to how it did so. Here, we show that the F-Box protein PALL interacts with phosphorylated Ribosomal protein S6 (RpS6) to promote its ubiquitylation and proteasomal degradation. This leads to RAC2 GTPase up-regulation and activation and F-actin remodeling that promotes efferocytosis. We further show that the specific role of PALL in efferocytosis is driven by its apoptotic cell-induced nuclear export. Finding a role for RpS6 in negatively regulating efferocytosis provides the opportunity to develop new strategies to regulate this process.

Ribosomal Protein S6 Phosphorylation

“…Finally, the PALL-dependent degradation of rpS6 leads to upregulation and activation of RAC2 GTPase that is followed by actin remodeling to promote efferocytosis (Xiao et al, 2015). Interestingly, rpS6 phosphorylation has been implicated in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in mammalian cells.…”

“…This complex promotes efficient apoptotic cell clearance in Drosophila (Silva et al, 2007). A study with Drosophila Schneider S2 cell line has unveiled the role of PALL in proteasomal degradation of rpS6 preferentially in its phosphorylated form (Xiao et al, 2015).…”

Phagocytosis genes nonautonomously promote developmental cell death in the Drosophila ovary

“…In macrophages, Ced-12 has been shown to function in a separate pathway from simu, a bridging molecule that acts upstream of draper (36). A number of other engulfment genes have been identified in Drosophila, and their molecular interactions are under active investigation (36)(37)(38)(39).…”

Lamellar events related to insulin‐like growth factor‐1 receptor signalling in two models relevant to endocrinopathic laminitis

“…Marked activation of RPS6 has been recognised in a broad range of epithelial cancers, and this protein is now considered to play a central role in epithelial disease (and provides a possible therapeutic target) [24,30]. Interestingly, activated RPS6 has recently been reported to disrupt cytoskeletal regulation [40,41]; this work, in combination with previous work reporting a loss of "stiffness" in epithelial tumour cells (probably due to cytoskeletal dysregulation) [42], indicates that RPS6-related signalling may play a role in the loss of lamellar epithelial morphology and epidermal lamellar stretching reported in EMSAL [3].…”