Distinct roles for APPL1 and APPL2 in regulating toll-like receptor 4 signaling in macrophages

Yeo, Jeremy C., Wall, Adam A., Luo, Lin, Condon, Nicholas D. and Stow, Jennifer L. (2016) Distinct roles for APPL1 and APPL2 in regulating toll-like receptor 4 signaling in macrophages. Traffic, 17 9: 1014-1026. doi:10.1111/tra.12415

Author Yeo, Jeremy C.
Wall, Adam A.
Luo, Lin
Condon, Nicholas D.
Stow, Jennifer L.
Title Distinct roles for APPL1 and APPL2 in regulating toll-like receptor 4 signaling in macrophages
Journal name Traffic   Check publisher's open access policy
ISSN 1600-0854
Publication date 2016-09-01
Year available 2016
Sub-type Article (original research)
DOI 10.1111/tra.12415
Open Access Status Not yet assessed
Volume 17
Issue 9
Start page 1014
End page 1026
Total pages 13
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Subject 1315 Structural Biology
1303 Biochemistry
1312 Molecular Biology
1311 Genetics
1307 Cell Biology
Abstract Macrophages are activated by contact with pathogens to mount innate immune defenses against infection. Toll-like receptor 4 (TLR4) at the macrophage surface recognizes and binds bacterial lipopolysaccharide (LPS), setting off signaling and transcriptional events that lead to the secretion of pro- and anti-inflammatory cytokines; these in turn control inflammatory and antimicrobial responses. Although the complex regulatory pathways downstream of TLR4 have been extensively studied, further molecules critical for modulating the resulting cytokine outputs remain to be characterized. Here we establish potential roles for APPL1 and 2 signaling adaptors as regulators of LPS/TLR4-induced signaling, transcription, and cytokine secretion. APPL1 and 2 are differentially localized to distinct signaling-competent membrane domains on the surface and in endocytic compartments of LPS-activated macrophages. By depleting cells of each adaptor respectively we show separate and opposing functions for APPL1 and 2 in Akt and MAPK signaling. Specifically, APPL2 has a dominant role in nuclear translocation of NF-KB p65 and it serves to constrain the secretion of pro- and anti-inflammatory cytokines. The APPLs, and in particular APPL2, are thus revealed as adaptors with important capacity to modulate inflammatory responses mounted by LPS/TLR4 during infection.
Keyword Cytokines
Signaling adaptors
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1003021
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 01 Oct 2016, 00:22:26 EST by Susan Allen on behalf of Institute for Molecular Bioscience