DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

Zhang, Qian; Dove, Christopher G.; Hor, Jyh Liang; Murdock, H. Moses; Strauss‐Albee, Dara M.; García, Juan Ruiz; Mandl, Judith N.; Grodick, Rachael A.; Jing, Huie; Chandler-Brown, Devon; Lenardo, Timothy E.; Crawford, Greg; Matthews, Helen; Freeman, Alexandra F.; Cornall, Richard J.; Germain, Ronald N.; Mueller, Scott N.; Su, Helen C.

doi:10.1084/jem.20141307

Cited by 145 publications

(83 citation statements)

References 77 publications

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“…In patients with DOCK8 deficiency, another primary immunodeficiency characterized by recurrent viral infections, abnormalities in actin dynamics lead to increased cell death during lymphocyte migration through tissues, resulting in an increased susceptibility to viral infections of the skin. 29 Similarly, patients with DOCK2 deficiency have both an increased susceptibility to invasive viral infections due to defective actin polymerization and T and B cell chemotaxis. 30 Therefore, in vitro cytotoxicity assays may not reflect the full impact of CORO1A S401fs on the host defense against viral pathogens in vivo , which requires the migration of T and NK cells to the site of infections.…”

Section: Discussionmentioning

confidence: 99%

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association

Yee

Massaad

Bainter

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Coronin-1A (CORO1A) is a regulator of actin dynamics important for T cell homeostasis. CORO1A deficiency causes T−B+NK+ severe combined immunodeficiency or T cell lymphopenia with severe viral infections. However, since all known human mutations in CORO1A abrogate protein expression, the role of the protein’s functional domains in host immunity is unknown. Objective To identify the cause of the primary immunodeficiency in two young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4+ T cell lymphopenia. Methods We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy controls. Results Both patients had CD4+ T cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA and specific antibody responses were normal. Whole genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last two C-terminal domains by replacing 61 a.a. with a novel 91 a.a. sequence. The CORO1AS401fs mutant was expressed in the patients’ lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes, but failed to oligomerize and had impaired cytoskeletal association. CORO1AS401fs was associated with increased F-actin accumulation in T cells, severely defective thymic output, and impaired T cell survival, but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oliogomerization and subcellular localization in T cell homeostasis. Conclusions We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T cell survival as well as in the defense against viral pathogens.

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Section: Discussionmentioning

confidence: 99%

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association

Yee

Massaad

Bainter

et al. 2016

Journal of Allergy and Clinical Immunology

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“…Amongst those, especially the identification of DOCK8 as a novel septin 7 interaction partner was a promising finding that could help to elucidate pathomechanisms in autoimmune diseases in our opinion. Like septin 7, DOCK8 is involved in the organization of actin cytoskeleton and regulates the structural integrity during immune cell trafficking 18,25 . Similar to septin 7 7 , DOCK8 levels were reduced in lymphocytes of ERU cases ( Figure 3) strengthening the functional overlap between these two molecules, which might affect the regulation of immune cell migration.…”

Section: Discussionmentioning

confidence: 99%

“…One of these interaction partners, dedicator of cytokinesis 8 (DOCK8), regulates various immune functions in lymphocytes [17][18][19] . DOCK8 was shown to be involved in immune synapse formation, lymphocyte migration and organization of cell shape 18 .…”

Section: Detection Of Dock8 As a Novel Interaction Partner Of Septinmentioning

confidence: 99%

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Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity

Schauer¹,

Kleinwort²,

Degroote³

et al. 2018

Preprint

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The GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in peripheral blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a novel DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter-and intracellular signaling in autoimmune disease.not peer-reviewed)

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“…It mediates cell differentiation, survival, adhesion and migration by coordinating actin cytoskeletal response through cell cycle 42(Cdc42) activation (2–6). DOCK8 is critical to the translocation of cutaneous dendritic cells to lymph nodes and the persistence of memory CD8 + T cells in the epidermis (7). In addition to its regulation of the actin cytoskeleton, DOCK8 regulates the differentiation of T helper (Th) cell subsets (8, 9).…”

Section: Introductionmentioning

confidence: 99%

DOCK8 Deficiency Presenting as an IPEX-Like Disorder

et al. 2017

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Purpose Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder. Methods Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (Treg) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole exome and Sanger sequencing. Results Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK- homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 –1G→A). Treg cell function was severely compromised by both DOCK8 mutations. Conclusion DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.

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DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

Cited by 145 publications

References 77 publications

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association

Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity

DOCK8 Deficiency Presenting as an IPEX-Like Disorder

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