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The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.

ABSTRACT: The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1-/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.

SUBMITTER: Salzer E

PROVIDER: S-EPMC7116756 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.

Salzer Elisabeth E Zoghi Samaneh S Kiss Máté G MG Kage Frieda F Rashkova Christina C Stahnke Stephanie S Haimel Matthias M Platzer René R Caldera Michael M Ardy Rico Chandra RC Hoeger Birgit B Block Jana J Medgyesi David D Sin Celine C Shahkarami Sepideh S Kain Renate R Ziaee Vahid V Hammerl Peter P Bock Christoph C Menche Jörg J Dupré Loïc L Huppa Johannes B JB Sixt Michael M Lomakin Alexis A Rottner Klemens K Binder Christoph J CJ Stradal Theresia E B TEB Rezaei Nima N Boztug Kaan K

Science immunology 20200701 49

The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1<sup ...[more]

PMID: 32646852

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Project description:Aspergillus fumigatus is the leading cause of invasive aspergillosis, which in immunocompromised patients results in a mortality rate as high as 90%. Earlier studies showed that HbxA is a global regulator in Aspergillus flavus affecting morphological development and secondary metabolism. Here, we determined its role in A. fumigatus, examining whether HbxA influences the regulation of asexual development, natural product biosynthesis, and virulence of this fungus. Our analysis demonstrated that removal of the hbxA gene caused a near-complete loss of conidial production in the mutant strain, as well as a slight reduction in colony growth. Other aspects of asexual development are affected, such as size and germination of conidia. Furthermore, we showed that in A. fumigatus, the loss of hbxA decreased the expression of the brlA central regulatory pathway involved in asexual development, as well as the expression of the "fluffy" genes flbB, flbD, and fluG HbxA was also found to regulate secondary metabolism, affecting the biosynthesis of multiple natural products, including fumigaclavines, fumiquinazolines, and chaetominine. In addition, using a neutropenic mouse infection model, hbxA was found to negatively impact the virulence of A. fumigatusIMPORTANCE The number of immunodepressed individuals is increasing, mainly due to the greater life expectancy in immunodepressed patients due to improvements in modern medical treatments. However, this population group is highly susceptible to invasive aspergillosis. This devastating illness, mainly caused by the fungus Aspergillus fumigatus, is associated with mortality rates reaching 90%. Treatment options for this disease are currently limited, and a better understanding of A. fumigatus genetic regulatory mechanisms is paramount for the design of new strategies to prevent or combat this infection. Our work provides new insight into the regulation of the development, metabolism, and virulence of this important opportunistic pathogen. The transcriptional regulatory gene hbxA has a profound effect on A. fumigatus biology, governing multiple aspects of conidial development. This is relevant since conidia are the main source of inoculum in Aspergillus infections. Importantly, hbxA also regulates the biosynthesis of secondary metabolites and the pathogenicity of this fungus.

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The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.

Publications

The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.

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