Defective Chemokine Signal Integration in Leukocytes Lacking Activator of G Protein Signaling 3 (AGS3)

Branham‐O'Connor, Melissa; Robichaux, William G.; Zhang, Xian-Kui; Cho, Hyeseon; Kehrl, John H.; Lanier, Stephen M.; Blumer, Joe B.

doi:10.1074/jbc.m113.515031

Cited by 25 publications

(19 citation statements)

References 77 publications

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“…The combined role of MyD88 and TRIF in the early induction and sustained activity of NF-κB activity TLR4 signaling (46) suggests that AGS3 may be a NF-κB target gene in macrophages. An involvement of NF-κB in the induction of AGS3 is also consistent with the increase in AGS3 noted in lymphocytes following antigen receptor crosslinking (26). …”

Section: Discussionsupporting

confidence: 80%

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Activator of G-Protein Signaling 3–Induced Lysosomal Biogenesis Limits Macrophage Intracellular Bacterial Infection

Vural

Khodor

Cheung

et al. 2016

The Journal of Immunology

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Many intracellular pathogens cause disease by subverting macrophage innate immune defense mechanisms. Intracellular pathogens actively avoid delivery to, or directly target lysosomes, the major intracellular degradative organelle. Here, we demonstrate that AGS3 (Activator of G-protein Signaling 3), a lipopolysaccharide inducible protein in macrophages, affects both lysosomal biogenesis and activity. AGS3 binds the Gi family of G proteins via its G-protein regulatory (GPR/GoLoco) motif stabilizing the Gα subunit in its GDP-bound conformation. Elevated AGS3 levels in macrophages limited the activity of the mammalian target of rapamycin (mTOR) pathway, a sensor of cellular nutritional status. This triggered the nuclear translocation of transcription factor EB (TFEB), a known activator of lysosomal gene transcription. In contrast, AGS3 deficient macrophages had increased mTOR activity, reduced TFEB activity, and a lower lysosomal mass. High levels of AGS3 in macrophages enhanced their resistance to infection by Burkholderia cenocepacia J2315, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus while AGS3 deficient macrophages were more susceptible. We conclude that LPS priming increases AGS3 levels, which enhances lysosomal function and increases the capacity of macrophages to eliminate intracellular pathogens.

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Section: Discussionsupporting

confidence: 80%

“…The levels of AGS3 are sensitive to a variety of stimuli in the cellular environment (25, 26). Here, we showed that lipopolysaccharide (LPS) stimulation raised AGS3 and LAMP-1 expression in both THP-1 cells and mouse bone marrow derived macrophages (BMDM, Fig.…”

Section: Resultsmentioning

confidence: 99%

Activator of G-Protein Signaling 3–Induced Lysosomal Biogenesis Limits Macrophage Intracellular Bacterial Infection

Vural

Khodor

Cheung

et al. 2016

The Journal of Immunology

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“…Several studies have implicated AGS3 in chemokine receptor signaling. Gpsm1 −/− mouse dendritic cells and lymphocytes exhibit suboptimal responds to chemokines in chemotaxis, calcium mobilization, and effector protein activation assays (74). Conversely, AGS3 may have a positive role in neutrophil chemotaxis.…”

Section: G-protein Regulatory Proteinsmentioning

confidence: 99%

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

Kehrl

2016

Biochemical Pharmacology

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Leukocyte chemoattractant receptors are members of the G-protein coupled receptor (GPCR) family. Signaling downstream of these receptors directs the localization, positioning and homeostatic trafficking of leukocytes; as well as their recruitment to, and their retention at, inflammatory sites. Ligand induced changes in the molecular conformation of chemoattractant receptors results in the engagement of heterotrimeric G-proteins, which promotes α subunits to undergo GTP/GDP exchange. This results in the functionally release of βγ subunits from the heterotrimers, thereby activating downstream effector molecules, which initiate leukocyte polarization, gradient sensing, and directional migration. Pertussis toxin ADP ribosylates Gαi subunits and prevents chemoattractant receptors from triggering Gαi nucleotide exchange. The use of pertussis toxin revealed the essential importance of Gαi subunit nucleotide exchange for chemoattractant receptor signaling. More recent studies have identified a range of regulatory mechanisms that target these receptors and their associated heterotrimeric G-proteins, thereby helping to control the magnitude, kinetics, and duration of signaling. A failure in these regulatory pathways can lead to impaired receptor signaling and immunopathology. The analysis of mice with targeted deletions of Gαi isoforms as well as some of these G-protein regulatory proteins is providing insights into their roles in chemoattractant receptor signaling.

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“…Among Group II AGS family members, AGS3 exhibits the greatest functional diversity and is implicated in a wide range of system and cellular functions, including adaptive responses to addiction and craving behavior, autophagy, membrane protein trafficking, metabolism, cardiovascular function, the renal response to injury (cytoprotection), ciliary biology, cystogenesis, polycystic kidney disease, asymmetric cell divisions and immune responsiveness (Blumer and Lanier, 2014;Blumer et al, 2012Blumer et al, , 2008Branham-O'Connor et al, 2014;Robichaux et al, 2017;Vural et al, 2016Vural et al, , 2010Bowers et al, 2004;Groves et al, 2010;Kwon et al, 2012;Regner et al, 2011;Sanada and Tsai, 2005;Saadaoui et al, 2017;Chishiki et al, 2017;Choi et al, 2016;Pedram et al, 2017;Singh et al, 2014;Yeh et al, 2013). How such functional diversity is achieved is not known, but may relate to the impact of the protein on basic cellular processes in a cell-and systemtype specific manner.…”

Section: Introductionmentioning

confidence: 99%

Role of G-proteins and phosphorylation in the distribution of AGS3 to cell puncta

Vural

Fadıllıoğlu

Keleşoğlu

et al. 2018

Journal of Cell Science

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Activator of G-protein signaling 3 (AGS3, also known as GPSM1) exhibits broad functional diversity and oscillates among different subcellular compartments in a regulated manner. AGS3 consists of a tetratricopeptide repeat (TPR) domain and a G-protein regulatory (GPR) domain. Here, we tested the hypothesis that phosphorylation of the AGS3 GPR domain regulates its subcellular distribution and functionality. In contrast to the cortical and/or diffuse nonhomogeneous distribution of wild-type (WT) AGS3, an AGS3 construct lacking all 24 potential phosphorylation sites in the GPR domain localized to cytosolic puncta. This change in localization was revealed to be dependent upon phosphorylation of a single threonine amino acid (T602). The punctate distribution of AGS3-T602A was rescued by co-expression of Gα i and Gα o but not Gα s or Gα q. Following treatment with alkaline phosphatase, both AGS3-T602A and WT AGS3 exhibited a gel shift in SDS-PAGE as compared to untreated WT AGS3, consistent with a loss of protein phosphorylation. The punctate distribution of AGS3-T602A was lost in an AGS3-A602T conversion mutant, but was still present upon T602 mutation to glutamate or aspartate. These results implicate dynamic phosphorylation as a discrete mechanism to regulate the subcellular distribution of AGS3 and associated functionality.

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Defective Chemokine Signal Integration in Leukocytes Lacking Activator of G Protein Signaling 3 (AGS3)

Cited by 25 publications

References 77 publications

Activator of G-Protein Signaling 3–Induced Lysosomal Biogenesis Limits Macrophage Intracellular Bacterial Infection

Activator of G-Protein Signaling 3–Induced Lysosomal Biogenesis Limits Macrophage Intracellular Bacterial Infection

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

Role of G-proteins and phosphorylation in the distribution of AGS3 to cell puncta

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