Abstract

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice.

Data availability

We are providing source files for the data shown in the main figures of the manuscript.

Article and author information

Author details

  1. Senem Aykul

    Skeletal Diseases TFA, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Senem Aykul, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  2. Richard A Corpina

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    No competing interests declared.
  3. Erich J Goebel

    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States
    Competing interests
    No competing interests declared.
  4. Camille J Cunanan

    Skeletal Diseases TFA, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    No competing interests declared.
  5. Alexandra Dimitriou

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    No competing interests declared.
  6. Hyonjong Kim

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Hyonjong Kim, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  7. Qian Zhang

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Qian Zhang, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  8. Ashique Rafique

    Therapeutic Antibodies, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Ashique Rafique, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  9. Raymond Leidich

    Bioassay, Molecular Biology, and Protein Development, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Raymond Leidich, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  10. Xin Wang

    Bioassay, Molecular Biology, and Protein Development, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Xin Wang, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  11. Joyce McClain

    Genome Engineering Technologies, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Joyce McClain, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  12. Johanna Jimenez

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Johanna Jimenez, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  13. Kalyan C Nannuru

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Kalyan C Nannuru, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  14. Nyanza J Rothman

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Nyanza J Rothman, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  15. John B Lees-Shepard

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    John B Lees-Shepard, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1275-5799
  16. Erik Martinez-Hackert

    Michigan State University, East Lansing, United States
    Competing interests
    No competing interests declared.
  17. Andrew J Murphy

    Research & Development, Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Andrew J Murphy, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
  18. Thomas B Thompson

    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States
    Competing interests
    No competing interests declared.
  19. Aris N Economides

    Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, United States
    For correspondence
    aris.economides@regeneron.com
    Competing interests
    Aris N Economides, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6508-8942
  20. Vincent Idone

    Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, United States
    For correspondence
    vincent.idone@regeneron.com
    Competing interests
    Vincent Idone, The author is an employee of Regeneron Pharmaceuticals, Inc. Regeneron is currently developing a monoclonal antibody that neutralizes Activin A (REGN2477) as a potential therapy in fibrodysplasia ossificans progressiva (see https://clinicaltrials.gov/ct2/show/NCT03188666)..

Funding

The authors declare that there was no funding for this work.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols.

Reviewing Editor

  1. Karen Lyons

Version history

  1. Received: December 19, 2019
  2. Accepted: June 8, 2020
  3. Accepted Manuscript published: June 9, 2020 (version 1)
  4. Version of Record published: June 30, 2020 (version 2)
  5. Version of Record updated: July 15, 2020 (version 3)

Copyright

© 2020, Aykul et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,827
    Page views
  • 377
    Downloads
  • 30
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Senem Aykul
  2. Richard A Corpina
  3. Erich J Goebel
  4. Camille J Cunanan
  5. Alexandra Dimitriou
  6. Hyonjong Kim
  7. Qian Zhang
  8. Ashique Rafique
  9. Raymond Leidich
  10. Xin Wang
  11. Joyce McClain
  12. Johanna Jimenez
  13. Kalyan C Nannuru
  14. Nyanza J Rothman
  15. John B Lees-Shepard
  16. Erik Martinez-Hackert
  17. Andrew J Murphy
  18. Thomas B Thompson
  19. Aris N Economides
  20. Vincent Idone
(2020)
Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop
eLife 9:e54582.
https://doi.org/10.7554/eLife.54582

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Maria Körner, Susanne R Meyer ... Alexander Buchberger
    Research Article Updated

    The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.

    1. Biochemistry and Chemical Biology
    2. Epidemiology and Global Health
    Takashi Sasaki, Yoshinori Nishimoto ... Yasumichi Arai
    Research Article

    Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60-70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85-89 years old) and centenarians.

    Methods: The study included 812 (women: 84.4%) for centenarians and 1,498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole genome sequencing or DNA microarray-imputation methods. LASSO and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression.

    Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p = 2.21 × 10-22) and ADIPOQ (p = 5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI.

    Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old.

    Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program 'Tonomachi Research Complex' Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.