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

AI Article Synopsis

  • UBQLNs 1, 2, and 4 are proteins that help manage protein quality in cells, and UBQLN2 is linked to neurodegenerative diseases like ALS/FTD by moving to the nucleus to clear damaged proteins.
  • Researchers identified a small protein called RTL8 that interacts with UBQLN2, helping it move to the nucleus and participate in protein quality control, especially under stress conditions like heat shock.
  • RTL8 enhances the stability of UBQLN2 and their co-location suggests RTL8 may play a key role in regulating UBQLN2's function in dealing with faulty nuclear proteins, marking a difference from other ubiquilins.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9376861PMC
http://dx.doi.org/10.1007/s00018-022-04170-zDOI Listing

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