TY - JOUR
T1 - RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control
AU - Mohan, Harihar Milaganur
AU - Trzeciakiewicz, Hanna
AU - Pithadia, Amit
AU - Crowley, Emily V.
AU - Pacitto, Regina
AU - Safren, Nathaniel
AU - Trotter, Bryce
AU - Zhang, Chengxin
AU - Zhou, Xiaogen
AU - Zhang, Yang
AU - Basrur, Venkatesha
AU - Paulson, Henry L.
AU - Sharkey, Lisa M.
N1 - Funding Information:
This work was supported by NIH 9R01NS096785-06, 1P30AG053760-01, The Amyotrophic Lateral Sclerosis Foundation and the UM Protein Folding Disease Initiative.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - Nuclear protein quality control
KW - RTL8
KW - UBQLN2
KW - Ubiquilin
KW - Ubiquitin proteasome system
UR - http://www.scopus.com/inward/record.url?scp=85125767355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125767355&partnerID=8YFLogxK
U2 - 10.1007/s00018-022-04170-z
DO - 10.1007/s00018-022-04170-z
M3 - Article
C2 - 35247097
AN - SCOPUS:85125767355
SN - 1420-682X
VL - 79
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 3
M1 - 176
ER -
