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bioRxiv · 10.1101/2024.11.06.622207

CDR2 is a dynein adaptor recruited by kinectin to regulate ER sheet organization

Teixeira, V.·Singh, K.·Gama, J. B.·Celestino, R.·Xavier de Carvalho, A.·Pereira, P.·Abreu, C. M.·Dantas, T. J.·Carter, A. P.·Gassmann, R.
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Abstract

The endoplasmic reticulum (ER) relies on the microtubule cytoskeleton for distribution and re-modelling of its extended membrane network, but how microtubule-based motors contribute to ER organization 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 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 eEF1B{beta} subunit of translation elongation factor 1 for binding to KTN1, and eEF1B{beta} 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.

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Teixeira, V., Singh, K., Gama, J. B., Celestino, R., Xavier de Carvalho, A., Pereira, P., Abreu, C. M., Dantas, T. J., Carter, A. P., Gassmann, R.. 2024-11-06. CDR2 is a dynein adaptor recruited by kinectin to regulate ER sheet organization. https://doi.org/10.1101/2024.11.06.622207

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