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RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control

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Abstract

The brain-expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. RTL8 also facilitates UBQLN2’s nuclear translocation during heat shock. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.

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The authors confirm that the data supporting the findings in this are available within the article, at repository links provided within the article, and within its supplementary files. The authors agree to share reagents, cell lines and animal models used in this study upon request.

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Acknowledgements

We thank Peter Howley and Huda Zoghbi for providing constructs, Huda Zoghbi for providing the UBQLN4 -/- mouse line and Ramanujan Hegde for providing the ubiquilin triple knockout cell line. We also thank Magdalena Ivanova and Sami Barmada for their helpful suggestions and critical feedback.

Funding

This work was supported by NIH 9R01NS096785-06, 1P30AG053760-01, The Amyotrophic Lateral Sclerosis Foundation and the UM Protein Folding Disease Initiative.

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Author notes

  1. Nathaniel Safren

    Present address: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

Authors and Affiliations

  1. Department of Neurology, University of Michigan, Ann Arbor, MI, 48109-2200, USA

    Harihar Milaganur Mohan, Hanna Trzeciakiewicz, Amit Pithadia, Emily V. Crowley, Regina Pacitto, Nathaniel Safren, Bryce Trotter, Henry L. Paulson & Lisa M. Sharkey

  2. Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, 48109-2200, USA

    Harihar Milaganur Mohan

  3. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109-2200, USA

    Chengxin Zhang, Xiaogen Zhou & Yang Zhang

  4. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Venkatesha Basrur

  5. Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, 48109-2200, USA

    Henry L. Paulson & Lisa M. Sharkey

Authors
  1. Harihar Milaganur Mohan
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  2. Hanna Trzeciakiewicz
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  3. Amit Pithadia
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  4. Emily V. Crowley
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  6. Nathaniel Safren
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  7. Bryce Trotter
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  8. Chengxin Zhang
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  9. Xiaogen Zhou
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  11. Venkatesha Basrur
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  12. Henry L. Paulson
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  13. Lisa M. Sharkey
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Contributions

Conceptualization: HM, AP, HP, LS. Methodology: HM, AP, HT, CZ, XZ, NS, VB, LS. Investigation: HM, AP, HT, CZ, XZ, EC, RP, NS, LS, BT. Writing: HM, HP, LS. Funding Acquisition: LS, HP. Resources: LS, YZ, HP. Supervision: HP, YZ, LS.

Corresponding authors

Correspondence to Henry L. Paulson or Lisa M. Sharkey.

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None declared.

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All animal experiments were conducted under the approval of The University of Michigan Institutional Animal Care & Use Committee, protocol number PRO00010103.

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Mohan, H.M., Trzeciakiewicz, H., Pithadia, A. et al. RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control. Cell. Mol. Life Sci. 79, 176 (2022). https://doi.org/10.1007/s00018-022-04170-z

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  • DOI: https://doi.org/10.1007/s00018-022-04170-z

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