HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions

Cook, Sara; Lenardo, Michael J.; Freeman, Alexandra F.

doi:10.1007/s10875-022-01327-0

Cited by 9 publications

(9 citation statements)

References 54 publications

(151 reference statements)

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“…Following WAS, several additional actin-regulatory genes that affect the ARP2/3 complex (Figure 5) have been implicated in primary immunodeficiencies that affect T cell function including ARPC1B 57,58 , ARPC5 59 , WIPF1, CORO1A, DOCK2, DOCK8, DOCK11, CDC42, RAC1, and RAC2 60 among others 61 . Genetic defects in the NCKAP1L (hem1) gene, which the Sixt group deleted to make WAVE-deficient leukocytes 45 , was also recently identified in human patients that exhibit a novel immunodeficiency 62,63 with recurrent infections and increased autoimmunity. Several murine models with conditional knockouts of the WAVE2 complex show immunological characteristics similar to AIDS including inverted CD4/CD8 ratios, skewing of T cells toward exhausted memory phenotypes, and enhanced autoimmunities 45,62,64 .…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Mediated Cortical Actin Disruption Mirrors ARP2/3 Defects Found in Primary T Cell Immunodeficiencies

Crater

Dunn

Nixon

et al. 2023

Preprint

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HIV-1 infection disrupts cortical actin, which balances osmotic and mechanical forces to provide an architectural scaffold that dictates T cell morphology and migration. HIV-1 infected cells have significantly less F-actin, lose their polarization, have reduced velocity and directionality, and lose their ability to traverse endothelial barriers and migrate in more complex dense environments. Although HIV-1 induced morphological changes in primary and oncogenic CD4+ T cells on 2D surfaces are reported to lose their polarization, infected cell migration in vivo show prolonged cell polarization. These discrepancies arise from cell type observed, environmental complexity of the system, and the time scale of observation. Here, we unify these disparate findings with time-lapse and ultrastructural microscopy showing that HIV-1 infection of primary CD4+ T cells causes at least five progressive morphological differences as a result of virally induced cortical cytoskeleton disruption. Although PAK2 and cofilin activity altered by Nef has previously been linked to these structural changes, viral mechanisms outside of Nef likely exist. Infection with a Nef-deleted (ΔNef) virus partially abrogated the dysfunctional phenotype in infected cells. Along with a recently reported lamellipodial blebbing phenotype4, we observe a fifth unreported pathological morphology distinct to HIV-1 infected CD4+ T cells. These two morphologies phenocopy migrating cells which contain genetic determinants of specific T cell primary immunodeficiencies that affect the actin cytoskeleton, particularly diseases affecting the ARP2/3 complex. The branched actin nucleator ARP2/3 is an important component of the lamellipodia during migration as well as the T cell immune synapse during activation and is frequently targeted by intracellular bacteria and enveloped viruses. The mechanically destabilized cellular cortex found in leukocytes from PID and following HIV-1 infection may provide context into cellular and systemic pathologies that drive similar clinical manifestations observed in primary and acquired immunodeficiencies.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Mediated Cortical Actin Disruption Mirrors ARP2/3 Defects Found in Primary T Cell Immunodeficiencies

Crater

Dunn

Nixon

et al. 2023

Preprint

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“…In 2020, nine pediatric patients from seven different lineages were identified with primary immune disorders (PID) secondary to loss-of-function mutations in the NCKAP1L gene encoding the Hem1 protein. HEM1 deficient patients were shown to have improper actin polymerization and networks leading to a clinical syndrome characterized by recurrent infections and autoimmunity ( 64 , 65 , 82 ) ( Figure 8 ) [see ( 62 ) for review]. The clinical picture in the patients identified so far varies; however most suffered from recurrent infections and hyperinflammation resulting in a high mortality rate at a young age.…”

Section: Human Disease Associated With Hem1 Variantsmentioning

confidence: 99%

“…Diagnosis of actin-related inborn errors of immunity (IEIs) such as HEM1 deficiency, can be challenging due to their clinical heterogeneity. Patients suspected of HEM1 deficiency based on their clinical presentation may undergo initial immune testing, such as immunoblotting, T and B cell activation studies, and neutrophil migration assays ( 62 ). Targeted gene sequencing panels allow for screening of already characterized IEI genes, such as HEM1, improving early diagnosis and medical management ( 3 ).…”

Section: Human Disease Associated With Hem1 Variantsmentioning

confidence: 99%

“…These differences in expression are also reflected by disparate associations with human disease. For example, LOF variants in the NCKAP1 gene encoding HEM2 in humans have been associated with neurodevelopmental disorders with features of autism ( 60 , 61 ), whereas LOF variants in NCKAP1L encoding HEM1 are associated with immunodeficiency, hyperinflammation, and autoimmunity [discussed below and reviewed in ( 62 )]. Hem Family members are evolutionarily conserved in Arabidopsis (Nap1), Dictyostelium (Nap1), C.elegans (GEX-3), and Drosophila melanogaster (KETTE).…”

Section: Activation Of Wasp and Wave Signaling Complexes And Actin Po...mentioning

confidence: 99%

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Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans

Christodoulou,

Tsai,

Suwankitwat

et al. 2024

Front. Immunol.

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Inborn errors of immunity (IEI) are a group of diseases in humans that typically present as increased susceptibility to infections, autoimmunity, hyperinflammation, allergy, and in some cases malignancy. Among newly identified genes linked to IEIs include 3 independent reports of 9 individuals from 7 independent kindreds with severe primary immunodeficiency disease (PID) and autoimmunity due to loss-of-function mutations in the NCKAP1L gene encoding Hematopoietic protein 1 (HEM1). HEM1 is a hematopoietic cell specific component of the WASp family verprolin homologous (WAVE) regulatory complex (WRC), which acts downstream of multiple immune receptors to stimulate actin nucleation and polymerization of filamentous actin (F-actin). The polymerization and branching of F-actin is critical for creating force-generating cytoskeletal structures which drive most active cellular processes including migration, adhesion, immune synapse formation, and phagocytosis. Branched actin networks at the cell cortex have also been implicated in acting as a barrier to regulate inappropriate vesicle (e.g. cytokine) secretion and spontaneous antigen receptor crosslinking. Given the importance of the actin cytoskeleton in most or all hematopoietic cells, it is not surprising that HEM1 deficient children present with a complex clinical picture that involves overlapping features of immunodeficiency and autoimmunity. In this review, we will provide an overview of what is known about the molecular and cellular functions of HEM1 and the WRC in immune and other cells. We will describe the common clinicopathological features and immunophenotypes of HEM1 deficiency in humans and provide detailed comparative descriptions of what has been learned about Hem1 disruption using constitutive and immune cell-specific mouse knockout models. Finally, we discuss future perspectives and important areas for investigation regarding HEM1 and the WRC.

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“…The actin remodeling that propels B cell spreading and IS formation involves a large network of proteins [15]. Human loss-of-function mutations in a number of actin-regulatory proteins, including the Wiskott-Aldrich syndrome protein (WASp), the WASp-interacting protein (WIP), the Arpc1B subunit of the Arp2/3 complex, Wdr1, Hem1, and DOCK8 lead to immune dysfunction syndromes that have been termed 'actinopathies' [16][17][18][19][20][21]. The loss of these proteins in humans and mice is associated with impaired B cell development, altered BCR signaling, defective B cell activation and Ab responses, and autoimmunity due to defective silencing of self-reactive B cells [22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

WAVE2 Regulates Actin-Dependent Processes Induced by the B Cell Antigen Receptor and Integrins

Bedi,

Choi,

Keane

et al. 2023

Cells

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B cell antigen receptor (BCR) signaling induces actin cytoskeleton remodeling by stimulating actin severing, actin polymerization, and the nucleation of branched actin networks via the Arp2/3 complex. This enables B cells to spread on antigen-bearing surfaces in order to increase antigen encounters and to form an immune synapse (IS) when interacting with antigen-presenting cells (APCs). Although the WASp, N-WASp, and WAVE nucleation-promoting factors activate the Arp2/3 complex, the role of WAVE2 in B cells has not been directly assessed. We now show that both WAVE2 and the Arp2/3 complex localize to the peripheral ring of branched F-actin when B cells spread on immobilized anti-Ig antibodies. The siRNA-mediated depletion of WAVE2 reduced and delayed B cell spreading on immobilized anti-Ig, and this was associated with a thinner peripheral F-actin ring and reduced actin retrograde flow compared to control cells. Depleting WAVE2 also impaired integrin-mediated B cell spreading on fibronectin and the LFA-1-induced formation of actomyosin arcs. Actin retrograde flow amplifies BCR signaling at the IS, and we found that depleting WAVE2 reduced microcluster-based BCR signaling and signal amplification at the IS, as well as B cell activation in response to antigen-bearing cells. Hence, WAVE2 contributes to multiple actin-dependent processes in B lymphocytes.

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HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions

Cited by 9 publications

References 54 publications

HIV-1 Mediated Cortical Actin Disruption Mirrors ARP2/3 Defects Found in Primary T Cell Immunodeficiencies

HIV-1 Mediated Cortical Actin Disruption Mirrors ARP2/3 Defects Found in Primary T Cell Immunodeficiencies

Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans

WAVE2 Regulates Actin-Dependent Processes Induced by the B Cell Antigen Receptor and Integrins

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