DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Harada, Yosuke; Tanaka, Yoshihiko; Terasawa, Masao; Pieczyk, Markus; Habiro, Katsuyoshi; Katakai, Tomoya; Hanawa-Suetsugu, Kyoko; Kukimoto-Niino, Mutsuko; Nishizaki, Terukazu; Shirouzu, Mikako; Duan, Xuefeng; Uruno, Takehito; Nishikimi, Akihiko; Sanematsu, Fumiyuki; Yokoyama, Shigeyuki; Stein, Jens V; Kinashi, Tatsuo; Fukui, Yoshihiro

doi:10.1182/blood-2012-01-407098

Cited by 207 publications

(256 citation statements)

References 47 publications

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“…In contrast, migration of Nlrp10 −/− DCs in the 3D collagen system was almost completely abrogated (Fig. 1A), similar to DOCK8-or CDC42-deficient DCs (9,10). Further, the Nlrp10 −/− strain exhibited other phenotypes that have been described in DOCK8-deficient mice, such as loss of marginal zone B cells (Fig.…”

Section: Resultsmentioning

confidence: 76%

“…DOCK8 is a guanine nucleotide exchange factor (GEF) that has two functional domains, DOCK homology region (DHR) 1 and DHR2 (8). In murine DCs, the DHR2 domain has been implicated in regulating the Rho GTPase CDC42 (cell division control protein 42 homolog), which in turn maintains cell polarity of mature DCs during migration (9,10). Furthermore, mice harboring inactivating mutations in Dock8 lack marginal zone B-cell development, long-term antibody production following immunization, and memory CD8 + T-cell responses to viral infections (11,12).…”

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confidence: 99%

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Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.D endritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4).NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)-binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10 −/− mice could ...

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Section: Resultsmentioning

confidence: 76%

mentioning

confidence: 99%

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…27 DOCK8, a member of the evolutionarily conserved DOCK family proteins, 28 was shown to bind to nucleotide-free CDC42 to mediate the GTP-GDP exchange reaction. Thereby, CDC42 is spatially activated at the plasma membrane, 29 where it plays a crucial role in apical differentiation and BBM formation. 30 Another GEF, the ArfGEF GBF-1, presented a strongly diminished phosphorylation status in Rap DTubule animals.…”

Section: Discussionmentioning

confidence: 99%

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells

Grahammer

Ramakrishnan

Rinschen

et al. 2016

JASN

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Renal proximal tubular cells constantly recycle nutrients to ensure minimal loss of vital substrates into the urine. Although most of the transport mechanisms have been discovered at the molecular level, little is known about the factors regulating these processes. Here, we show that mTORC1 and mTORC2 specifically and synergistically regulate PTC endocytosis and transport processes. Using a conditional mouse genetic approach to disable nonredundant subunits of mTORC1, mTORC2, or both, we showed that mice lacking mTORC1 or mTORC1/mTORC2 but not mTORC2 alone develop a Fanconi-like syndrome of glucosuria, phosphaturia, aminoaciduria, low molecular weight proteinuria, and albuminuria. Interestingly, proteomics and phosphoproteomics of freshly isolated kidney cortex identified either reduced expression or loss of phosphorylation at critical residues of different classes of specific transport proteins. Functionally, this resulted in reduced nutrient transport and a profound perturbation of the endocytic machinery, despite preserved absolute expression of the main scavenger receptors, MEGALIN and CUBILIN. Our findings highlight a novel mTOR-dependent regulatory network for nutrient transport in renal proximal tubular cells.

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“…In addition, the activation of both WAS proteins is strongly promoted by interaction with phosphatidyl inositol (4, 5)-bisphosphate (PIP2) in the plasma membrane 40,41 and by tyrosine phosphorylation by BTK and SRC-family kinases 42 Studies from non-B cells show that WIPF1 protects WAS proteins from degradation, but it also stabilizes actin filaments independently of WAS 61 and mediates the binding of WASL to NCK proteins 62 , and the binding of WAS to DOCK8 63 . DOCK8 is a GEF for CDC42 that associates with the plasma membrane through binding to phosphatidyl inositol (3, 4, 5)-trisphosphate (PIP3) 64 . Mutations in DOCK8 cause immunodeficiency with impaired B cell synapse formation and activation 65 , suggesting that the WAS-WIPF1-DOCK8-CDC42 complex underlies many of the positive functions of WAS in B cells.…”

Section: [H1] Structure Of the Cortical Cytoskeletonmentioning

confidence: 99%

Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

125

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The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton couples extensively to B cell receptor (BCR) signalling pathways and its defects can either enhance or suppress B cell activation. Recent insights from single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion, and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also play a role in the adaptation of B cell subsets to specialized tasks during antibody responses.3

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DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Cited by 207 publications

References 47 publications

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells

Cytoskeletal control of B cell responses to antigens

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