Rab31 and APPL2 enhance FcγR-mediated phagocytosis through PI3K/Akt signaling in macrophages

Abstract

Rab31 recruits APPL2 to regulate phagocytic cup closure and FcγR signaling pathways via production of PI(3,4,5)P3 in macrophages. APPL2 is poised to activate macrophages and act as a counterpoint to APPL1 in FcγR-mediated PI3K/Akt signaling. New locations and roles are found for Rab31 and APPL2 by which they contribute to innate immune functions.

Distinct Roles for APPL1 and APPL2 in Regulating Toll‐like Receptor 4 Signaling in Macrophages

“…The signaling endosome niche, defined and demarcated by APPLs in many cell types, is an important site for receptor internalization and signaling and it precedes the better‐known, EEA1 and PI(3)P double‐positive early endosomes . Live cell imaging also revealed the transient association of APPL1 in macropinosomes forming from the surface after LPS activation with loss of APPL1 prior to mCherry‐2xFYVE‐labeling, reflecting the well‐known dissociation of APPL1 from signaling endosomes and phagosomes as they mature and acquire PI(3)P. In contrast, membrane‐recruited APPL2 in macrophages is more prominent on cell surface membrane ruffles and it has a sustained association with macropinosomes including retention on the PI(3)P endosomes (Figure ) and phagosomes . The range and identities of the different endosomal compartments that act as TLR4 signaling sites in macrophages is currently not clear, but they do include macropinosomes where the TRIF and TRAM adaptors have been localized .…”

Appl1andAppl2are Expendable for Mouse Development But Are Essential for HGF-Induced Akt Activation and Migration in Mouse Embryonic Fibroblasts

“…Recent in vitro studies on Appl1 and Appl2 by several labs, using RNAi or expression constructs, have generated paradoxical results (Broussard et al, 2012; Miaczynska et al, 2004; Saito et al, 2007; Tu et al, 2011; Yeo et al, 2015). Unbiased genetic evidence is therefore needed to better understand the function of Appl proteins.…”

“…However, the influence of Appl1/2 proteins on Akt activation appears to be highly context dependent. Specifically, some reports indicate that Appl proteins facilitate Akt activation during insulin signaling or during phagocytosis (Saito et al, 2007; Yeo et al, 2015). Other groups have reported converse findings, with Appl impairing cell migration and osteoclastogenesis by suppressing AKT (Broussard et al, 2012; Tu et al, 2011).…”

“…In muscle cells, APPL2 can act as a negative regulator of adiponectin and insulin signaling by competing with APPL1 in the binding of adiponectin receptors and by sequestrating APPL1 from these two pathways (Wang et al, 2009). In contrast, Appl2 is required for Akt activation during phagocytosis of macrophages (Yeo et al, 2015). …”

The cell surface environment for pathogen recognition and entry

“…The PtdIns(3,4,5)P 3 produced in ruffles then persists after closure and through the early stages of formation of macropinosomes and phagocytic cups 18 . These phosphoinositide transitions can be observed using probes such as the pleckstrin homology domain of protein kinase B (AKT) 29 , 30 . The phosphoinositides also recruit effector proteins to the membrane such as transporter associated with antigen processing 1 and Lowe oculocerebrorenal syndrome protein, which can influence the dynamics of the cytoskeleton and subsequent compartment maturation 22 …”