RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control.
Adaptor Proteins, Signal Transducing
/ deficiency
Amino Acid Sequence
Animals
Autophagy-Related Proteins
/ deficiency
Brain
/ metabolism
Carrier Proteins
/ genetics
Cell Nucleolus
/ metabolism
HEK293 Cells
Humans
Membrane Proteins
/ chemistry
Mice
Mice, Knockout
Nuclear Proteins
/ genetics
Protein Binding
Protein Isoforms
/ chemistry
Recombinant Proteins
/ biosynthesis
Sequence Alignment
Temperature
Ubiquitin
/ metabolism
Nuclear protein quality control
RTL8
UBQLN2
Ubiquilin
Ubiquitin proteasome system
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
05 Mar 2022
05 Mar 2022
Historique:
received:
19
04
2021
accepted:
25
01
2022
revised:
17
01
2022
entrez:
5
3
2022
pubmed:
6
3
2022
medline:
15
3
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35247097
doi: 10.1007/s00018-022-04170-z
pii: 10.1007/s00018-022-04170-z
pmc: PMC9376861
mid: NIHMS1822727
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Autophagy-Related Proteins
0
Carrier Proteins
0
Membrane Proteins
0
Nuclear Proteins
0
Protein Isoforms
0
RTL8C protein, human
0
Recombinant Proteins
0
UBQLN1 protein, human
0
UBQLN1 protein, mouse
0
UBQLN2 protein, human
0
UBQLN4 protein, human
0
Ubiquitin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
176Subventions
Organisme : NIA NIH HHS
ID : P30 AG053760
Pays : United States
Organisme : NIH HHS
ID : 1P30AG053760-01
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS093469
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS122302
Pays : United States
Organisme : NIH HHS
ID : 9R01NS096785-06
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS096785
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072931
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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