Rab Family Proteins Regulate the Endosomal Trafficking and Function of RGS4

Bastin, Guillaume; Heximer, Scott P.

doi:10.1074/jbc.m113.466888

Cited by 28 publications

(22 citation statements)

References 93 publications

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“…In order to examine the involvement of LE in TLR3 activation, we expressed GFP tagged dominant-negative Rab7 (DN-Rab7) in mouse macrophage cell-line RAW 264.7. Expression of DN-Rab7 blocks vesicular traffic to LE and therefore has been widely utilized to study function of LE during various physiological/biological processes (51). As a control we expressed GFP and GFP tagged wild type Rab7 (WT-Rab7) in RAW 264.7 cells.…”

Section: Resultsmentioning

confidence: 99%

Regulation of TLR3 Activation by S100A9

Tsai

Segovia

Chang

et al. 2015

The Journal of Immunology

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Recognition of viral dsRNA by endosomal toll-like receptor 3 (TLR3) activates innate immune response during virus infection. Trafficking of TLR3 to the endo-lysosomal (EL) compartment arising from fusion of late endosome (LE) with lysosome is required for recognition and detection of Pathogen Associated Molecular Patterns (PAMP). PAMP detection results in activation of TLR3-dependent signaling cascade. Existing knowledge about the mechanism(s) and cellular factor(s) governing TLR3 trafficking is limited. In the current study we have identified intracellular S100A9 protein as a critical regulator of TLR3 trafficking. S100A9 was required for maturation of TLR3 containing early endosome (EE) into LE, the compartment that fuses with lysosome to form EL compartment. Drastic reduction in cytokine production was observed in S100A9 knockout (KO) primary macrophages following RNA virus infection and treatment of cells with polyIC (a dsRNA mimetic that acts as a TLR3 agonist). Mechanistic studies revealed co-localization and interaction of S100A9 with TLR3 following polyIC treatment. S100A9-TLR3 interaction was critical for maturation of TLR3 containing EE into LE since TLR3 could not be detected in the LE of polyIC treated S100A9 KO macrophages. Subsequently, TLR3 failed to co-localize with its agonist (i.e. biotin-labeled polyIC) in S100A9 deficient macrophages. The in vivo physiological role of S100A9 was evident from loss of cytokine production in polyIC treated S100A9 KO mice. Thus, we have identified intracellular S100A9 as a regulator of TLR3 signaling and demonstrated that S100A9 functions during pre-TLR3 activation stages by facilitating maturation of TLR3 containing EE into LE.

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Section: Resultsmentioning

confidence: 99%

Regulation of TLR3 Activation by S100A9

Tsai

Segovia

Chang

et al. 2015

The Journal of Immunology

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“…These were all characterized by GO molecular function that placed Rab5 and −7 proteins as those engaged in GTP catabolic processes, endocytosis and small GTPase-mediated signal transduction pathways. The molecular functions for both endosomal-linked proteins are GDP/GTPase activity and protein binding [ 41 ]. LAMP1 is associated with autophagy, the establishment of protein localization to cell organelles, golgi to lysosome transport, protein transport along microtubules and regulation of natural killer cell degranulation cytotoxic activities.…”

Section: Discussionmentioning

confidence: 99%

“…Its activation promotes focal adhesion disassembly, migration and invasiveness in tumor cells [ 43 ] and its knockdown decreases cell motility and invasion by an integrin-mediated signaling pathway [ 44 ]. Moreover, it has been indicated that Rab5, −7 and −11, affect RGS4 trafficking through plasma membrane recycling or endosomes [ 41 ] and are used by the drug particles and the virus in a coordinated manner. This was seen for other viral infections such as hepatitis B virus, which can affect Rab5 and −7 expressions and use pathways for viral transport from early to mature endosomes.…”

Section: Discussionmentioning

confidence: 99%

Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages

et al. 2015

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BackgroundLong-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.ResultsWe applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated in opposing manners by the virus and the nanoATV, likely by viral clearance. Paired-sample z-scores, of the proteomic data sets, showed up- and down- regulation of Rab-linked endolysosomal proteins. NanoART and native ATV treated uninfected cells showed limited effects. The data was confirmed by Western blot. DAVID and KEGG bioinformatics analyses of proteomic data showed relationships between secretory, mobility and phagocytic cell functions and virus and particle trafficking.ConclusionsWe posit that modulation of endolysosomal pathways by antiretroviral nanoparticles provides a strategic path to combat HIV infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-014-0133-5) contains supplementary material, which is available to authorized users.

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“…The Rab family GTPases are typical markers for identifying intracellular vesicular traffic routes of membrane proteins. For example, Rab5, Rab7, and Rab11 are widely used for tracing early, late, and recycling endosomal pathway, respectively [31,32]. HEK-293 cells were stimulated for various periods of time (0-60 min) with melatonin (100 nM), followed by fluorescence analysis of colocalization between MTNR1A and various Rab isoforms (Fig.…”

Section: Spatio-temporal Changes Of Mtnr1a Internalization After Melamentioning

confidence: 99%

Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner

Jiang

Long

et al. 2015

Mol Neurobiol

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Valproate exposure is associated with increased risks of autism spectrum disorder. To date, the mechanistic details of disturbance of melatonin receptor subtype 1 (MTNR1A) internalization upon valproate exposure remain elusive. By expressing epitope-tagged receptors (MTNR1A-EGFP) in HEK-293 and Neuro-2a cells, we recorded the dynamic changes of MTNR1A intracellular trafficking after melatonin treatment. Using time-lapse confocal microscopy, we showed in living cells that valproic acid interfered with the internalization kinetics of MTNR1A in the presence of melatonin. This attenuating effect was associated with a decrease in the phosphorylation of PKA (Thr197) and ERK (Thr202/Tyr204). VPA treatment did not alter the whole-cell currents of cells with or without melatonin. Furthermore, fluorescence resonance energy transfer imaging data demonstrated that valproic acid reduced the melatonin-initiated association between YFP-labeled β-arrestin 2 and CFP-labeled MTNR1A. Together, we suggest that valproic acid influences MTNR1A intracellular trafficking and signaling in a β-arrestin 2-dependent manner.

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Rab Family Proteins Regulate the Endosomal Trafficking and Function of RGS4

Cited by 28 publications

References 93 publications

Regulation of TLR3 Activation by S100A9

Regulation of TLR3 Activation by S100A9

Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages

Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner

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