Coronin 2B Regulates Neuronal Migration via Rac1-Dependent Multipolar-Bipolar Transition.

In the developing cortex, excitatory neurons migrate along the radial fibers to their final destinations and build up synaptic connection with each other to form functional circuitry. The shaping of neuronal morphologies by actin cytoskeleton dynamics is crucial for neuronal migration. However, it is largely unknown how the distribution and assembly of the F-actin cytoskeleton are coordinated. In the present study, we found that an actin regulatory protein, coronin 2B, is indispensable for the transition from a multipolar to bipolar morphology during neuronal migration in ICR mice of either sex. Loss of coronin 2B led to heterotopic accumulation of migrating neurons in the intermediate zone along with reduced dendritic complexity and aberrant neuronal activity in the cortical plate. This was accompanied by increased seizure susceptibility, suggesting the malfunction of cortical development in coronin 2B-deficient brains. Coronin 2B knockdown disrupted the distribution of the F-actin cytoskeleton at the leading processes, while the migration defect in coronin 2B-deficient neurons was partially rescued by overexpression of Rac1 and its downstream actin-severing protein, cofilin. Our results collectively reveal the physiological function of coronin 2B during neuronal migration whereby it maintains the proper distribution of activated Rac1 and the F-actin cytoskeleton.SIGNIFICANCE STATEMENT Deficits in neuronal migration during cortical development result in various neurodevelopmental disorders (e.g., focal cortical dysplasia, periventricular heterotopia, epilepsy, etc.). Most signaling pathways that control neuronal migration process converge to regulate actin cytoskeleton dynamics. Therefore, it is important to understand how actin dynamics is coordinated in the critical processes of neuronal migration. Herein, we report that coronin 2B is a key protein that regulates neuronal migration through its ability to control the distribution of the actin cytoskeleton and its regulatory signaling protein Rac1 during the multipolar-bipolar transition in the intermediate zone, providing insights into the molecular machinery that drives the migration process of newborn neurons.

Actin filament debranching regulates cell polarity during cell migration and asymmetric cell division.

The formation of the branched actin networks is essential for cell polarity, but it remains unclear how the debranching activity of actin filaments contributes to this process. Here, we showed that an evolutionarily conserved coronin family protein, the Caenorhabditis elegans POD-1, debranched the Arp2/3-nucleated actin filaments in vitro. By fluorescence live imaging analysis of the endogenous POD-1 protein, we found that POD-1 colocalized with Arp2/3 at the leading edge of the migrating C. elegans neuroblasts. Conditional mutations of POD-1 in neuroblasts caused aberrant actin assembly, disrupted cell polarity, and impaired cell migration. In C. elegans one-cell-stage embryos, POD-1 and Arp2/3, moved together during cell polarity establishment, and inhibition of POD-1 blocked Arp2/3 motility and affected the polarized cortical flow, leading to symmetric segregation of cell fate determinants. Together, these results indicate that F-actin debranching organizes actin network and cell polarity in migrating neuroblasts and asymmetrically dividing embryos.

Turgor-dependent and coronin-mediated F-actin dynamics drive septin disc-to-ring remodeling in the blast fungus Magnaporthe oryzae.

The fungus Magnaporthe oryzae uses a specialized pressure-generating infection cell called an appressorium to break into rice leaves and initiate disease. Appressorium functionality is dependent on the formation of a cortical septin ring during its morphogenesis, but precisely how this structure assembles is unclear. Here, we show that F-actin rings are recruited to the circumference of incipient septin disc-like structures in a pressure-dependent manner, and that this is necessary for their contraction and remodeling into rings. We demonstrate that the structural integrity of these incipient septin discs requires both an intact F-actin and microtubule cytoskeleton and provide fundamental new insight into their functional organization within the appressorium. Lastly, using proximity-dependent labeling, we identify the actin modulator coronin as a septin-proximal protein and show that F-actin-mediated septin disc-to-ring remodeling is perturbed in the genetic absence of coronin. Taken together, our findings provide new insight into the dynamic remodeling of infection-specific higher-order septin structures in a globally significant fungal plant pathogen.

Emerging functions of cytoskeletal proteins in immune diseases.

Immune cells are especially dependent on the proper functioning of the actin cytoskeleton, and both innate and adaptive responses rely on it. Leukocytes need to adhere not only to substrates but also to cells in order to form synapses that pass on instructions or kill infected cells. Neutrophils literally squeeze their cell body during blood extravasation and efficiently migrate to the inflammatory focus. Moreover, the development of immune cells requires the remodeling of their cytoskeleton as it depends on, among other processes, adhesive contacts and migration. In recent years, the number of reports describing cytoskeletal defects that compromise the immune system has increased immensely. Furthermore, a new emerging paradigm points toward a role for the cellular actin content as an essential component of the so-called homeostasis-altering molecular processes that induce the activation of innate immune signaling pathways. Here, we review the role of critical actin-cytoskeleton-remodeling proteins, including the Arp2/3 complex, cofilin, coronin and WD40-repeat containing protein 1 (WDR1), in immune pathophysiology, with a special focus on autoimmune and autoinflammatory traits.

Proteomic Fingerprint of Lung Fibrosis Progression and Response to Therapy in Bleomycin-Induced Mouse Model.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy are still poorly understood. In this work, the molecular fingerprint of fibrosis progression and response to nintedanib treatment have been investigated by mass spectrometry-based bottom-up proteomics in paraffin-embedded lung tissues from bleomycin-induced (BLM) pulmonary fibrosis mice. Our proteomics results unveiled that (i) samples clustered depending on the tissue fibrotic grade (mild, moderate, and severe) and not on the time course after BLM treatment; (ii) the dysregulation of different pathways involved in fibrosis progression such as the complement coagulation cascades, advanced glycation end products (AGEs) and their receptors (RAGEs) signaling, the extracellular matrix-receptor interaction, the regulation of actin cytoskeleton, and ribosomes; (iii) Coronin 1A (Coro1a) as the protein with the highest correlation when evaluating the progression of fibrosis, with an increased expression from mild to severe fibrosis; and (iv) a total of 10 differentially expressed proteins (padj-value ≤ 0.05 and Fold change ≤-1.5 or ≥1.5), whose abundance varied in the base of the severity of fibrosis (mild and moderate), were modulated by the antifibrotic treatment with nintedanib, reverting their trend. Notably, nintedanib significantly restored lactate dehydrogenase B (Ldhb) expression but not lactate dehydrogenase A (Ldha). Notwithstanding the need for further investigations to validate the roles of both Coro1a and Ldhb, our findings provide an extensive proteomic characterization with a strong relationship with histomorphometric measurements. These results unveil some biological processes in pulmonary fibrosis and drug-mediated fibrosis therapy.

Mycobacterium tuberculosis and its clever approaches to escape the deadly macrophage.

Mycobacterium tuberculosis (Mt.b), a deadly disease causer, is a facultative parasite. This microorganism has developed several methods to defend itself, once internalized within specialised vacuoles in the macrophages. A wide array of receptors like the complement receptor mannose receptors, scavenger receptor assists the entry of the microbe within the phagocytic macrophages. However, Mt.b is clever enough to protect itself from the hostile environment of the macrophage thereby prevailing within it. The microbe can efficiently inhibit processes like phagosome-lysosome fusion, acidification of phagosomes, release of proinflammatory cytokines and stop crucial events like apoptosis. Additionally, it also adopts resistance to killing by reactive oxygen intermediates and reactive nitrogen intermediates. There are multiple genes both in host and the pathogen which are involved in this successful survival of Mt.b. The regulation of phagolysosome fusion is mediated by proteins such as Coronin, TlyA, SapM, PnkG, EsxH. The microbe has certain mechanisms to even acquire iron from the host cell, to withstand iron deprivation as a mode of host's defence mechanism. This review focuses on the various defensive adaptations acquired by Mt.b for fighting against the deprived conditions existing within the macrophages and their capability of proliferating successfully within it, thereby resulting in a diseased condition.

Coronin1C Is a GDP-Specific Rab44 Effector That Controls Osteoclast Formation by Regulating Cell Motility in Macrophages.

Osteoclasts are multinucleated bone-resorbing cells that are formed by the fusion of macrophages. Recently, we identified Rab44, a large Rab GTPase, as an upregulated gene during osteoclast differentiation that negatively regulates osteoclast differentiation. However, the molecular mechanisms by which Rab44 negatively regulates osteoclast differentiation remain unknown. Here, we found that the GDP form of Rab44 interacted with the actin-binding protein, Coronin1C, in murine macrophages. Immunoprecipitation experiments revealed that the interaction of Rab44 and Coronin1C occurred in wild-type and a dominant-negative (DN) mutant of Rab44, but not in a constitutively active (CA) mutant of Rab44. Consistent with these findings, the expression of the CA mutant inhibited osteoclast differentiation, whereas that of the DN mutant enhanced this differentiation. Using a phase-contrast microscope, Coronin1C-knockdown osteoclasts apparently impaired multinuclear formation. Moreover, Coronin1C knockdown impaired the migration and chemotaxis of RAW-D macrophages. An in vivo experimental system demonstrated that Coronin1C knockdown suppresses osteoclastogenesis. Therefore, the decreased cell formation and fusion of Coronin1C-depleted osteoclasts might be due to the decreased migration of Coronin1C-knockdown macrophages. These results indicate that Coronin1C is a GDP-specific Rab44 effector that controls osteoclast formation by regulating cell motility in macrophages.

Catastrophic actin filament bursting by cofilin, Aip1, and coronin.

Cofilin is an actin filament severing protein necessary for fast actin turnover dynamics. Coronin and Aip1 promote cofilin-mediated actin filament disassembly, but the mechanism is somewhat controversial. An early model proposed that the combination of cofilin, coronin, and Aip1 disassembled filaments in bursts. A subsequent study only reported severing. Here, we used EM to show that actin filaments convert directly into globular material. A monomer trap assay also shows that the combination of all three factors produces actin monomers faster than any two factors alone. We show that coronin accelerates the release of Pi from actin filaments and promotes highly cooperative cofilin binding to actin to create long stretches of polymer with a hypertwisted morphology. Aip1 attacks these hypertwisted regions along their sides, disintegrating them into monomers or short oligomers. The results are consistent with a catastrophic mode of disassembly, not enhanced severing alone.

Coronin-1 levels in patients with tuberculosis.

Background & objectives: Despite advances in diagnostics and therapeutics, tuberculosis (TB) is widely prevalent and contributes to a significant burden of illness in both developing and developed nations. The present study was aimed to assess the role of coronin in TB patients and healthy controls. Coronin is a leucocyte-specific protein that is actively recruited in mycobacterial phagolysosomes, where it inhibits lysosomal delivery of Mycobacterium by activating a calcium-dependent phosphatase-calcineurin. Methods: In the study, 100 newly diagnosed cases of TB (pulmonary and extra-pulmonary) and healthy controls were prospectively enrolled over one year and the levels of coronin-1a in these patients and controls were measured by quantitative PCR (qPCR). Results: A total of 100 TB patients and 100 healthy individuals as controls were assessed. There were 59 patients with extra-pulmonary TB (EPTB) and 41 of pulmonary TB (PTB). In 47 per cent of patients, corroborative histopathological evidence of TB was also available. Significantly higher values of coronin-1a were observed in TB patients (19.94±2.61) than in healthy controls (16.09±1.91) (P<0.001). Interpretation & conclusions: Coronin 1a appears to play an important role in the TB disease pathophysiology and agents developed against coronin may have a role in the treatment of TB. Further studies are required to assess if coronin-1a levels are elevated in non-tubercular infective a etiologies and whether these can be a potential drug target in patients with TB.

Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility.

Drug resistance is an obstacle to global malaria control, as evidenced by the recent emergence and rapid spread of delayed artemisinin (ART) clearance by mutant forms of the PfKelch13 protein in Southeast Asia. Identifying genetic determinants of ART resistance in African-derived parasites is important for surveillance and for understanding the mechanism of resistance. In this study, we carried out long-term in vitro selection of two recently isolated West African parasites (from Pikine and Thiès, Senegal) with increasing concentrations of dihydroartemisinin (DHA), the biologically active form of ART, over a 4-y period. We isolated two parasite clones, one from each original isolate, that exhibited enhanced survival to DHA in the ring-stage survival assay. Whole-genome sequence analysis identified 10 mutations in seven different genes. We chose to focus on the gene encoding PfCoronin, a member of the WD40-propeller domain protein family, because mutations in this gene occurred in both independent selections, and the protein shares the ß-propeller motif with PfKelch13 protein. For functional validation, when pfcoronin mutations were introduced into the parental parasites by CRISPR/Cas9-mediated gene editing, these mutations were sufficient to reduce ART susceptibility in the parental lines. The discovery of a second gene for ART resistance may yield insights into the molecular mechanisms of resistance. It also suggests that pfcoronin mutants could emerge as a nonkelch13 type of resistance to ART in natural settings.

Molecular Pathogenesis of the Coronin Family: CORO2A Facilitates Migration and Invasion Abilities in Oral Squamous Cell Carcinoma.

In humans, the coronin family is composed of seven proteins containing WD-repeat domains that regulate actin-based cellular processes. Some members of the coronin family are closely associated with cancer cell migration and invasion. The Cancer Genome Atlas (TCGA) analysis revealed that CORO1C, CORO2A, and CORO7 were significantly upregulated in oral squamous cell carcinoma (OSCC) tissues (p < 0.05). Moreover, the high expression of CORO2A was significantly predictive of the 5-year survival rate of patients with OSCC (p = 0.0203). Overexpression of CORO2A was detected in OSCC clinical specimens by immunostaining. siRNA-mediated knockdown of CORO2A suppressed cancer cell migration and invasion abilities. Furthermore, we investigated the involvement of microRNAs (miRNAs) in the molecular mechanism underlying CORO2A overexpression in OSCC cells. TCGA analysis confirmed that tumor-suppressive miR-125b-5p and miR-140-5p were significantly downregulated in OSCC tissues. Notably, these miRNAs bound directly to the 3'-UTR of CORO2A and controlled CORO2A expression in OSCC cells. In summary, we found that aberrant expression of CORO2A facilitates the malignant transformation of OSCC cells, and that downregulation of tumor-suppressive miRNAs is involved in CORO2A overexpression. Elucidation of the interaction between genes and miRNAs will help reveal the molecular pathogenesis of OSCC.

Coronin 1B regulates the TNFα-induced apoptosis of HUVECs by mediating the interaction between TRADD and FADD.

Coronin 1B is an actin-binding protein that plays important roles in actin-dependent cellular processes. We previously reported that coronin 1B is involved in vascular endothelial cell growth factor-induced migration of human umbilical vein endothelial cells (HUVECs). However, the role of coronin 1B in tumor necrosis factor alpha (TNFα)-induced endothelial cell apoptosis remained unknown. In this study, we investigated whether coronin 1B affects TNFα-induced HUVEC apoptosis and sought to elucidate the mechanism by which coronin 1B regulates this cellular process. Depletion of coronin 1B by siRNA transfection decreased TNFα-induced apoptosis of HUVECs, as determined by MTT, terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase-3 activity assays. Coronin 1B depletion also decreased caspase-8 cleavage via a JNK-independent pathway. Coronin 1B interacted with Fas-associated death domain protein (FADD) in both a plasmid overexpression system in HEK293T cells and at the endogenous protein level in TNFα-stimulated HUVECs. Immunoprecipitation and in situ proximity ligation assays showed that coronin 1B depletion diminished the interaction between TNFα-induced TNF receptor-1-associated death domain protein (TRADD) and FADD, suggesting that coronin 1B is required for the TNFα-induced TRADD and FADD interaction and subsequent caspase-8/caspase-3 cascade activation, ultimately leading to apoptosis.

miR-26 suppresses renal cell cancer via down-regulating coronin-3.

Coronin-3 (coronin-1C), a homotrimer F-actin-binding protein, has been reported to be important for metastasis in several types of cancers such as lung cancer, gastric cancer, and breast cancer. Here, we present an investigation of the expression and function of coronin-3 in renal cell cancer for the first time. We also confirmed that miR-26 directly targets coronin-3 and down-regulates its expression by western blot assay and dual-luciferase reporter system. The results of MTT and colony formation assay showed that miR-26 suppressed cell proliferation. Wound healing and transwell assay revealed that miR-26 inhibited migration and invasion of renal cancer cell. Moreover, overexpression of coronin-3 could reverse the miR-26-induced inhibition in cell growth and metastasis. Thus, our study suggests that coronin-3 should serve as a potential therapeutic target in renal cell cancer and provide a candidate for miRNA therapy.

Surveillance of genetic markers associated with Plasmodium falciparum resistance to artemisinin-based combination therapy in Pakistan, 2018-2019.

BACKGROUND: The spread of artemisinin resistance in the Greater Mekong Subregion of Southeast Asia poses a significant threat for current anti-malarial treatment guidelines globally. The aim of this study was to assess the current prevalence of molecular markers of drug resistance in Plasmodium falciparum in the four provinces with the highest malaria burden in Pakistan, after introducing artemether-lumefantrine as first-line treatment in 2017. METHODS: Samples were collected during routine malaria surveillance in Punjab, Sindh, Baluchistan, and Khyber Pakhtunkhwa provinces of Pakistan between January 2018 and February 2019. Plasmodium falciparum infections were confirmed by rapid diagnostic test or microscopy. Plasmodium falciparum positive isolates (n = 179) were screened by Sanger sequencing for single nucleotide polymorphisms (SNPs) in the P. falciparum kelch 13 (pfk13) propeller domain and in P. falciparum coronin (pfcoronin). SNPs in P. falciparum multidrug resistance 1 (pfmdr1) N86Y, Y184F, D1246Y and P. falciparum chloroquine resistance transporter (pfcrt) K76T were genotyped by PCR-restriction fragment length polymorphism. RESULTS: No artemisinin resistance associated SNPs were identified in the pfk13 propeller domain or in pfcoronin. The pfmdr1 N86, 184F, D1246 and pfcrt K76 alleles associated with reduced lumefantrine sensitivity were present in 83.8% (150/179), 16.9% (29/172), 100.0% (173/173), and 8.4% (15/179) of all infections, respectively. The chloroquine resistance associated pfcrt 76T allele was present in 98.3% (176/179) of infections. CONCLUSION: This study provides an update on the current prevalence of molecular markers associated with reduced P. falciparum sensitivity to artemether and/or lumefantrine in Pakistan, including a first baseline assessment of polymorphisms in pfcoronin. No mutations associated with artemisinin resistance were observed in pfk13 or pfcoronin. However, the prevalence of the pfmdr1 N86 and D1246 alleles, that have been associated with decreased susceptibility to lumefantrine, remain high. Although clinical and molecular data suggest that the current malaria treatment guidelines for P. falciparum are presently effective in Pakistan, close monitoring for artemisinin and lumefantrine resistance will be critical to ensure early detection and enhanced containment of emerging ACT resistance spreading across from Southeast Asia.

Biochemical and immunocytochemical characterization of coronins in platelets.

Rapid reorganization of the actin cytoskeleton in response to receptor-mediated signaling cascades allows platelets to transition from a discoid shape to a flat spread shape upon adhesion to damaged vessel walls. Coronins are conserved regulators of the actin cytoskeleton turnover but they also participate in signaling events. To gain a better picture of their functions in platelets we have undertaken a biochemical and immunocytochemical investigation with a focus on Coro1. We found that class I coronins Coro1, 2 and 3 are abundant in human and mouse platelets whereas little Coro7 can be detected. Coro1 is mainly cytosolic, but a significant amount associates with membranes in an actin-independent manner and does not translocate from or to the membrane fraction upon exposure to thrombin, collagen or prostacyclin. Coro1 rapidly translocates to the Triton insoluble cytoskeleton upon platelet stimulation with thrombin or collagen. Coro1, 2 and 3 show a diffuse cytoplasmic localization with discontinuous accumulation at the cell cortex and actin nodules of human platelets, where all three coronins colocalize. Our data are consistent with a role of coronins as integrators of extracellular signals with actin remodeling and suggests a high extent of functional overlap among class I coronins in platelets.

MiR-206 may suppress non-small lung cancer metastasis by targeting CORO1C.

OBJECT: Non-small lung cancer (NSCLC), with a poor 5-year survival rate (16%), is the major type of lung cancer. Metastasis has been identified as the main factor that leads to NSCLC therapy failure. MiR-206 is a metastasis suppressor in many cancers, including colorectal cancer, renal cell carcinoma and breast cancer. However, the role of miR-206 in NSCLC metastasis and the underlying mechanism are still obscure. METHODS: Quantitative reverse-transcription PCR (q-RT-PCR) assay was used to detect miR-206 mRNA of NSCLC tissues and lung cancer lines. The MTT assay, scratch wound healing assay, transwell migration assay and transwell invasion assay were conducted to illuminate the effect of miR-206 on A549 cells' proliferation, migration and invasion. Gaussia luciferase reporter assay, q-RT-PCR and western blotting assay were used to explore the underlying mechanism. Also, the A549 xenograft model was conducted to evaluate the anti-tumor effect of miR-206 in vivo. RESULTS: The results showed that miR-206 expression was decreased in NSCLC tissues and lung cancer cells. Further research demonstrated that miR-206 inhibited the proliferation, migration and invasion of A549 cells via negatively regulating Coronin-1C (CORO1C), and CORO1C deletion significantly rescues the miR-206 mediated inhibitory effect on A549 cells. Moreover, miR-206 exhibited a perfect anti-tumor effect in the A549 xenograft model. CONCLUSION: Our study reveals that miR-206 functions as a tumor metastasis suppressor and sheds new light on the clinical significance of miR-206 in NSCLC therapy.

Interactome and F-Actin Interaction Analysis of Dictyostelium discoideum Coronin A.

Coronin proteins are evolutionary conserved WD repeat containing proteins that have been proposed to carry out different functions. In Dictyostelium, the short coronin isoform, coronin A, has been implicated in cytoskeletal reorganization, chemotaxis, phagocytosis and the initiation of multicellular development. Generally thought of as modulators of F-actin, coronin A and its mammalian homologs have also been shown to mediate cellular processes in an F-actin-independent manner. Therefore, it remains unclear whether or not coronin A carries out its functions through its capacity to interact with F-actin. Moreover, the interacting partners of coronin A are not known. Here, we analyzed the interactome of coronin A as well as its interaction with F-actin within cells and in vitro. Interactome analysis showed the association with a diverse set of interaction partners, including fimbrin, talin and myosin subunits, with only a transient interaction with the minor actin10 isoform, but not the major form of actin, actin8, which was consistent with the absence of a coronin A-actin interaction as analyzed by co-sedimentation from cells and lysates. In vitro, however, purified coronin A co-precipitated with rabbit muscle F-actin in a coiled-coil-dependent manner. Our results suggest that an in vitro interaction of coronin A and rabbit muscle actin may not reflect the cellular interaction state of coronin A with actin, and that coronin A interacts with diverse proteins in a time-dependent manner.

Coronin 1 Is Required for Integrin ß2 Translocation in Platelets.

Remodeling of the actin cytoskeleton is one of the critical events that allows platelets to undergo morphological and functional changes in response to receptor-mediated signaling cascades. Coronins are a family of evolutionarily conserved proteins implicated in the regulation of the actin cytoskeleton, represented by the abundant coronins 1, 2, and 3 and the less abundant coronin 7 in platelets, but their functions in these cells are poorly understood. A recent report revealed impaired agonist-induced actin polymerization and cofilin phosphoregulation and altered thrombus formation in vivo as salient phenotypes in the absence of an overt hemostasis defect in vivo in a knockout mouse model of coronin 1. Here we show that the absence of coronin 1 is associated with impaired translocation of integrin ß2 to the platelet surface upon stimulation with thrombin while morphological and functional alterations, including defects in Arp2/3 complex localization and cAMP-dependent signaling, are absent. Our results suggest a large extent of functional overlap among coronins 1, 2, and 3 in platelets, while aspects like integrin ß2 translocation are specifically or predominantly dependent on coronin 1.

PtpA, a secreted tyrosine phosphatase from Staphylococcus aureus, contributes to virulence and interacts with coronin-1A during infection.

Secretion of bacterial signaling proteins and adaptation to the host, especially during infection, are processes that are often linked in pathogenic bacteria. The human pathogen Staphylococcus aureus is equipped with a large arsenal of immune-modulating factors, allowing it to either subvert the host immune response or to create permissive niches for its survival. Recently, we showed that one of the low-molecular-weight protein tyrosine phosphatases produced by S. aureus, PtpA, is secreted during growth. Here, we report that deletion of ptpA in S. aureus affects intramacrophage survival and infectivity. We also observed that PtpA is secreted during macrophage infection. Immunoprecipitation assays identified several host proteins as putative intracellular binding partners for PtpA, including coronin-1A, a cytoskeleton-associated protein that is implicated in a variety of cellular processes. Of note, we demonstrated that coronin-1A is phosphorylated on tyrosine residues upon S. aureus infection and that its phosphorylation profile is linked to PtpA expression. Our results confirm that PtpA has a critical role during infection as a bacterial effector protein that counteracts host defenses.

Human inborn errors of the actin cytoskeleton affecting immunity: way beyond WAS and WIP.

Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology.