CDR2 is a dynein adaptor recruited by kinectin to regulate ER sheet organization
The ER relies on the microtubule cytoskeleton for the organization of its extended membrane network, but how microtubule-based motors contribute remains unclear. Using biochemical and cell-based assays, we identify cerebellar degeneration-related protein 2 (CDR2) and its paralog CDR2-like (CDR2L), onconeural antigens with poorly understood functions, as ER adaptors for cytoplasmic dynein-1 (dynein). We demonstrate in human cancer cells that CDR2 is recruited by the integral ER membrane protein kinectin (KTN1) and that double knockout of CDR2 and CDR2L enhances KTN1-dependent ER sheet stacking, reversal of which by exogenous CDR2 requires its dynein-binding CC1 box motif. Exogenous CDR2 expression additionally promotes CC1 box-dependent clustering of ER sheets near centrosomes. CDR2 competes with the eEF1Bβ subunit of translation elongation factor 1 for binding to KTN1, and eEF1Bβ knockdown increases endogenous CDR2 levels on ER sheets, inducing their centrosome-proximal clustering. Our study describes a novel molecular pathway that implicates dynein in ER sheet organization and may be involved in the pathogenesis of paraneoplastic cerebellar degeneration.
Authors
- Kashish Singh (ORCID: https://orcid.org/0000-0002-9891-8148)
- Andrew P. Carter (ORCID: https://orcid.org/0000-0001-7292-5430)
- Tiago J. Dantas (ORCID: https://orcid.org/0000-0002-0120-4895)
- Carla M. C. Abreu (ORCID: https://orcid.org/0000-0002-8070-8388)
- Reto Gassmann (ORCID: https://orcid.org/0000-0002-0360-2977)
- Ricardo Celestino (ORCID: https://orcid.org/0000-0002-9605-6433)
- José B. Gama (ORCID: https://orcid.org/0000-0002-7011-1502)
- Ana Xavier Carvalho (ORCID: https://orcid.org/0000-0002-2256-7134)
- Paulo S. Pereira
- Vanessa Teixeira (ORCID: https://orcid.org/0000-0003-1971-1999)
- M. V. B. Moreira (ORCID: https://orcid.org/0000-0001-8544-6770)
Institutions
- MRC Laboratory of Molecular Biology (GB)
- Universidade do Porto (PT)
- Instituto de Biología Molecular y Celular de Rosario (AR)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- Instituto de Biología Molecular y Celular de Plantas (ES)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1083/jcb.202411034
- Citations
- 2
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 2.30
Funders
- Ministério da Ciência, Tecnologia e Ensino Superior
- National Institutes of Health
- University of California, San Francisco
- Fundação para a Ciência e a Tecnologia
- National Institute of Allergy and Infectious Diseases