TY - JOUR
T1 - Evidence of TRK-Fused Gene (TFG1) function in the ubiquitin-proteasome system
AU - Yagi, Takuya
AU - Ito, Daisuke
AU - Suzuki, Norihiro
N1 - Funding Information:
This work was supported by Eisai Co. Ltd. , the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 24890228 , 23591254 ), and Kurata Memorial Hitachi Science and Technology Foundation . We are grateful to Ms. Tamao Kitamura (Department of Neurology, School of Medicine, Keio University) for technical assistance, Dr. Anjon Audhya (The University of Wisconsin, USA) for providing GFP-tagged human TFG1 pCMV, Dr. Andrew Bateman (McGill University of Medicine, Canada) for providing PRGN, Dr. Ron Kopito (Stanford University, USA) for providing GFP degron, and Dr. Masayuki Miura (Tokyo University, Japan) for providing pCAX-F-XBP1-ΔDBD-Venus. We thank the Collaborative Research Resources, School of Medicine, Keio University, for technical assistance.
PY - 2014/6
Y1 - 2014/6
N2 - A heterozygous mutation in the TRK-Fused Gene (TFG1) has recently been identified in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). TFG1 protein is reportedly localized at endoplasmic reticulum (ER) exit sites and modulates ER export, but the mechanism of its action in neurodegeneration remains unclear. To clarify the molecular pathogenesis of HMSN-P, we examined the biochemical and cellular characteristics of wild-type and mutant (P285L) TFG1 in vitro. A coexpression study of human TFG1 and ER substrates, which are degraded by the ubiquitin-proteasome system (UPS), showed that TFG1 is an inhibitory regulator of the UPS. Deletion mutant constructs revealed that the proline/glutamine-rich domain in TFG1 was critical for regulation of the UPS and proper localization at ER exit sites. Furthermore, overexpression of wild-type TFG1 increased ubiquitination of ER-resident proteins and led to ER stress. Mutant (P285L) TFG1, which is in the proline/glutamine-rich domain, enhanced the inhibitory effect on the UPS and the level of ER stress. These data provide new pathological insights into HMSN-P, and we suspect that the pathogenesis is tightly associated with disruption of intracellular protein homeostasis and ER stress.
AB - A heterozygous mutation in the TRK-Fused Gene (TFG1) has recently been identified in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). TFG1 protein is reportedly localized at endoplasmic reticulum (ER) exit sites and modulates ER export, but the mechanism of its action in neurodegeneration remains unclear. To clarify the molecular pathogenesis of HMSN-P, we examined the biochemical and cellular characteristics of wild-type and mutant (P285L) TFG1 in vitro. A coexpression study of human TFG1 and ER substrates, which are degraded by the ubiquitin-proteasome system (UPS), showed that TFG1 is an inhibitory regulator of the UPS. Deletion mutant constructs revealed that the proline/glutamine-rich domain in TFG1 was critical for regulation of the UPS and proper localization at ER exit sites. Furthermore, overexpression of wild-type TFG1 increased ubiquitination of ER-resident proteins and led to ER stress. Mutant (P285L) TFG1, which is in the proline/glutamine-rich domain, enhanced the inhibitory effect on the UPS and the level of ER stress. These data provide new pathological insights into HMSN-P, and we suspect that the pathogenesis is tightly associated with disruption of intracellular protein homeostasis and ER stress.
KW - Amyotrophic lateral sclerosis
KW - Endoplasmic reticulum stress
KW - Neuropathy
KW - TRK-fused gene
KW - Ubiquitin-Proteasome system
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U2 - 10.1016/j.nbd.2014.02.011
DO - 10.1016/j.nbd.2014.02.011
M3 - Article
C2 - 24613659
AN - SCOPUS:84896935063
SN - 0969-9961
VL - 66
SP - 83
EP - 91
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -