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Cited by 20Erythrocyte Function and PathophysiologyHemoglobinopathies and Related DisordersBlood properties and coagulation

Hematopoietic Protein-1 Regulates the Actin Membrane Skeleton and Membrane Stability in Murine Erythrocytes

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Chan, Maia M., Wooden, Jason M., Tsang, Mark, Gilligan, Diana M., Hirenallur-S, Dinesh K., Finney, Greg L., Rynes, Eric, MacCoss, Michael +3 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0054902PMC PMC3570531
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Abstract

Hematopoietic protein-1 (Hem-1) is a hematopoietic cell specific member of the WAVE (Wiskott-Aldrich syndrome verprolin-homologous protein) complex, which regulates filamentous actin (F-actin) polymerization in many cell types including immune cells. However, the roles of Hem-1 and the WAVE complex in erythrocyte biology are not known. In this study, we utilized mice lacking Hem-1 expression due to a non-coding point mutation in the Hem1 gene to show that absence of Hem-1 results in microcytic, hypochromic anemia characterized by abnormally shaped erythrocytes with aberrant F-actin foci and decreased lifespan. We find that Hem-1 and members of the associated WAVE complex are normally expressed in wildtype erythrocyte progenitors and mature erythrocytes. Using mass spectrometry and global proteomics, Coomassie staining, and immunoblotting, we find that the absence of Hem-1 results in decreased representation of essential erythrocyte membrane skeletal proteins including α- and β- spectrin, dematin, p55, adducin, ankyrin, tropomodulin 1, band 3, and band 4.1. Hem1⁻/⁻ erythrocytes exhibit increased protein kinase C-dependent phosphorylation of adducin at Ser724, which targets adducin family members for dissociation from spectrin and actin, and subsequent proteolysis. Increased adducin Ser724 phosphorylation in Hem1⁻/⁻ erythrocytes correlates with decreased protein expression of the regulatory subunit of protein phosphatase 2A (PP2A), which is required for PP2A-dependent dephosphorylation of PKC targets. These results reveal a novel, critical role for Hem-1 in the homeostasis of structural proteins required for formation and stability of the actin membrane skeleton in erythrocytes.

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  • Reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion.

    “indicating that reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion [8, 10, 12, 33].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [33]

    The Results report disrupted organization of the actin membrane skeleton in Hem1-null erythrocytes, and the Discussion links this disruption to reduced membrane stability (page numbers unavailable). The paper does not report vesicular hypersecretion or show that a weakened actin barrier facilitates it. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing HEM1-deficient patients to bacterial infections.

    “Like mouse models of HEM1 deficiency, defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing patients to bacterial infections [32–35].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [33]

    The Introduction (page unavailable) reports defects in immune-cell development and function in Hem1-null mice, and the Discussion describes a role for immune-cell actin structures in protection against pathogens. The paper does not establish defects in migration and phagocytosis across all three named cell types or show that HEM1-deficient patients are predisposed to bacterial infections. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Multiple investigations found elevated surface CD107a levels after CD8+ T cell degranulation and lower cortical actin thickness.

    “Multiple investigations found elevated surface CD107a levels after CD8 + T cell degranulation and lower cortical actin thickness”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [33]

    The Results passage concerns actin-related protein changes in Hem1-deficient murine erythrocytes, not CD8+ T cells. Searches for CD107a, CD8+ T-cell degranulation, and cortical actin thickness found no passage addressing the claimed findings; the Discussion’s general statement about actin polymerization in immune cells does not establish them. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Chan, M. M., Wooden, J. M., Tsang, M., Gilligan, D. M., Hirenallur-S, D. K., Finney, G. L., Rynes, E., MacCoss, M., Ramirez, J. A., Park, H., & Iritani, B. M.
Affiliations
  • University of Washington (US)
  • Bloodworks Northwest (US)
Corresponding author
Iritani, Brian M.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-02-12
Volume
8
Issue
2
Pages
e54902
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0054902
PMC
PMC3570531
OpenAlex
W2068899912
Cited by
20
References
1
Citations by year
2025: 3 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 2
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (K01OD010554, AG013280, GM103533)
  • National Institute on Aging (P30AG013280)
  • National Institute of General Medical Sciences (P41GM103533)
Topics
  • Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
Keywords
WAVE complex, erythrocytes, F-actin polymerization, protein phosphatase 2A, spectrin, erythrocyte membrane stability, microcytic anemia, erythrocyte lifespan, protein kinase C
MeSH terms
Actins, Animals, Erythrocyte Membrane, Phosphorylation, Stem Cells, Time Factors, Gene Deletion, Adaptor Proteins, Signal Transducing, Wiskott-Aldrich Syndrome Protein Family, Mice, Transcriptome

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