Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells

  1. Jaroslaw Cendrowski  Is a corresponding author
  2. Marta Kaczmarek
  3. Michał Mazur
  4. Katarzyna Kuzmicz-Kowalska
  5. Kamil Jastrzebski
  6. Marta Brewinska-Olchowik
  7. Agata Kominek
  8. Katarzyna Piwocka
  9. Marta Miaczynska  Is a corresponding author
  1. International Institute of Molecular and Cell Biology in Warsaw, Poland
  2. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Poland

Abstract

Intracellular transport undergoes remodeling upon cell differentiation, which involves cell type-specific regulators. Bone morphogenetic protein 2-inducible kinase (BMP2K) has been potentially implicated in endocytosis and cell differentiation but its molecular functions remained unknown. We discovered that its longer (L) and shorter (S) splicing variants regulate erythroid differentiation in a manner unexplainable by their involvement in AP-2 adaptor phosphorylation and endocytosis. However, both variants interact with SEC16A and could localize to the juxtanuclear secretory compartment. Variant-specific depletion approach showed that BMP2K isoforms constitute a BMP2K-L/S regulatory system that controls the distribution of SEC16A and SEC24B as well as SEC31A abundance at COPII assemblies. Finally, we found L to promote and S to restrict autophagic degradation and erythroid differentiation. Hence, we propose that BMP2K-L and BMP2K-S differentially regulate abundance and distribution of COPII assemblies as well as autophagy, possibly thereby fine-tuning erythroid differentiation.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD013542

The following data sets were generated

Article and author information

Author details

  1. Jaroslaw Cendrowski

    Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
    For correspondence
    jcendrowski@iimcb.gov.pl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8579-7279
  2. Marta Kaczmarek

    Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4939-6299
  3. Michał Mazur

    Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5087-4409
  4. Katarzyna Kuzmicz-Kowalska

    Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  5. Kamil Jastrzebski

    Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  6. Marta Brewinska-Olchowik

    Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  7. Agata Kominek

    Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  8. Katarzyna Piwocka

    Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  9. Marta Miaczynska

    Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
    For correspondence
    miaczynska@iimcb.gov.pl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0031-5267

Funding

Narodowe Centrum Nauki (UMO-2011/02/A/NZ3/00149)

  • Jaroslaw Cendrowski
  • Katarzyna Kuzmicz-Kowalska
  • Kamil Jastrzebski
  • Marta Miaczynska

Fundacja na rzecz Nauki Polskiej (POIR.04.04.00-00-20CE/16-00)

  • Marta Kaczmarek
  • Kamil Jastrzebski
  • Marta Miaczynska

Fundacja na rzecz Nauki Polskiej (POIR.04.04.00-00-1C54/16-00)

  • Jaroslaw Cendrowski
  • Michał Mazur

Fundacja na rzecz Nauki Polskiej (POIR.04.04.00-00-23C2/17-00)

  • Katarzyna Piwocka

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Elizabeth A Miller, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: May 2, 2020
  2. Accepted: August 13, 2020
  3. Accepted Manuscript published: August 14, 2020 (version 1)
  4. Version of Record published: September 4, 2020 (version 2)

Copyright

© 2020, Cendrowski 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

  • 2,118
    Page views
  • 242
    Downloads
  • 4
    Citations

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

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. Jaroslaw Cendrowski
  2. Marta Kaczmarek
  3. Michał Mazur
  4. Katarzyna Kuzmicz-Kowalska
  5. Kamil Jastrzebski
  6. Marta Brewinska-Olchowik
  7. Agata Kominek
  8. Katarzyna Piwocka
  9. Marta Miaczynska
(2020)
Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells
eLife 9:e58504.
https://doi.org/10.7554/eLife.58504

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Sara Scinicariello, Adrian Soderholm ... Gijs A Versteeg
    Research Article

    Tristetraprolin (TTP) is a critical negative immune regulator. It binds AU-rich elements in the untranslated-regions of many mRNAs encoding pro-inflammatory mediators, thereby accelerating their decay. A key but poorly understood mechanism of TTP regulation is its timely proteolytic removal: TTP is degraded by the proteasome through yet unidentified phosphorylation-controlled drivers. In this study, we set out to identify factors controlling TTP stability. Cellular assays showed that TTP is strongly lysine-ubiquitinated, which is required for its turnover. A genetic screen identified the ubiquitin E3 ligase HUWE1 as a strong regulator of TTP proteasomal degradation, which we found to control TTP stability indirectly by regulating its phosphorylation. Pharmacological assessment of multiple kinases revealed that HUWE1-regulated TTP phosphorylation and stability was independent of the previously characterized effects of MAPK-mediated S52/S178 phosphorylation. HUWE1 function was dependent on phosphatase and E3 ligase binding sites identified in the TTP C-terminus. Our findings indicate that while phosphorylation of S52/S178 is critical for TTP stabilization at earlier times after pro-inflammatory stimulation, phosphorylation of the TTP C-terminus controls its stability at later stages.

    1. Cell Biology
    Agustin Leonardo Lujan, Ombretta Foresti ... Vivek Malhotra
    Research Article

    We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen (ROS), and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.