The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

Wang, I-Fan; Chang, Hsin-Li; Hou, Shu-Jin; Liou, Gunn‐Guang; Way, Tzong‐Der; Shen, Che Kun James

doi:10.1038/ncomms1766

Cited by 76 publications

(108 citation statements)

References 50 publications

(61 reference statements)

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“…Interestingly, the prion-like domain of TDP-43 is required for TDP-43 splicing regulation, but not for transcription activation (28). Our study reveals a significant difference between the functional relevance of the prion-like domain of FUS and that of TDP-43, suggesting that FUS and TDP-43 may function differently in the nucleus.…”

Section: Chromatin Binding Of Fus Is Required For Its Function Of Regmentioning

confidence: 69%

Self-assembled FUS binds active chromatin and regulates gene transcription

Yang

Gál

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

121

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Fused in sarcoma (FUS) is a DNA/RNA binding protein and mutations in FUS cause a subset of familial ALS. Most ALS mutations are clustered in the C-terminal nuclear localization sequence of FUS and consequently lead to the accumulation of protein inclusions in the cytoplasm. It remains debatable whether loss of FUS normal function in the nucleus or gain of toxic function in the cytoplasm plays a more critical role in the ALS etiology. Moreover, the physiological function of FUS in the nucleus remains to be fully understood. In this study, we found that a significant portion of nuclear FUS was bound to active chromatin and that the ALS mutations dramatically decreased FUS chromatin binding ability. Functionally, the chromatin binding is required for FUS transcription activation, but not for alternative splicing regulation. The N-terminal QGSY (glutamine-glycine-serine-tyrosine)-rich region (amino acids 1-164) mediates FUS self-assembly in the nucleus of mammalian cells and the self-assembly is essential for its chromatin binding and transcription activation. In addition, RNA binding is also required for FUS self-assembly and chromatin binding. Together, our results suggest a functional assembly of FUS in the nucleus under physiological conditions, which is different from the cytoplasmic inclusions. The ALS mutations can cause loss of function in the nucleus by disrupting this assembly and chromatin binding. FUS is a multifunctional protein and has been reported to play a role in various aspects of RNA metabolism (6), including transcription regulation and alternative splicing. FUS was initially identified in liposarcomas as part of a fusion protein (7,8) in which the N-terminal domain of FUS (amino acid 1-266) is recombined to transcription factor CHOP at its N terminus. The FUS-CHOP fusion protein activates the transcription of oncogenes and promotes tumorigenesis (9, 10). In familial ALS, most mutations are clustered in the C-terminal nuclear localization sequence (NLS) of FUS and consequently cause the mislocalization of FUS protein from the nucleus to the cytoplasm and the accumulation of protein inclusions (11-13). Such observations suggest two potential disease-causing mechanisms: loss of FUS normal function in the nucleus and gain of toxic function in the cytoplasm. It remains to be determined which mechanism plays a more critical role in ALS etiology and the two mechanisms are not necessarily exclusive of each other.Cytoplasmic FUS inclusions resemble stress granules, indicated by colocalization of FUS with different stress granule components (11,12). Stress granules are temporary cellular structures containing RNAs and proteins from suspended translation apparatus (14). Stress granule formation promotes cell survival under stressed conditions by redistributing translation resources. Compromised stress granule response in the presence of FUS mutants is considered a contributing factor to motor neuron dysfunction (15).Although t...

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Section: Chromatin Binding Of Fus Is Required For Its Function Of Regmentioning

confidence: 69%

Self-assembled FUS binds active chromatin and regulates gene transcription

Yang

Gál

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

121

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“…The TDP-43 C-terminus is prone to spontaneous aggregation, and pathological TDP-43 aggregates from diseased brains can function as seeds to induce seed-dependent TDP-43 aggregation in cells 17 . Recently, we demonstrated that a GQN-rich domain in the nonamyloid disease protein TDP-43 could be functionally substituted with the yeast prion domain Sup35N, suggesting that amyloid and non-amyloid disease proteins have similar folded domains in healthy cells 18 . This domain participates in a novel type of protein interaction in which the native TDP-43 C-terminus physically interacts with either itself or the folded yeast prion domain Sup35 to form dynamic insoluble aggregates 18 .…”

mentioning

confidence: 99%

“…Recently, we demonstrated that a GQN-rich domain in the nonamyloid disease protein TDP-43 could be functionally substituted with the yeast prion domain Sup35N, suggesting that amyloid and non-amyloid disease proteins have similar folded domains in healthy cells 18 . This domain participates in a novel type of protein interaction in which the native TDP-43 C-terminus physically interacts with either itself or the folded yeast prion domain Sup35 to form dynamic insoluble aggregates 18 . The aggregation-prone nature of TDP-43 affects its known roles in cellular processes such as subcellular localization, cystic fibrosis transmembrane conductance regulator exon skipping and protein stability 18 .…”

mentioning

confidence: 99%

“…This domain participates in a novel type of protein interaction in which the native TDP-43 C-terminus physically interacts with either itself or the folded yeast prion domain Sup35 to form dynamic insoluble aggregates 18 . The aggregation-prone nature of TDP-43 affects its known roles in cellular processes such as subcellular localization, cystic fibrosis transmembrane conductance regulator exon skipping and protein stability 18 . The TDP-43 C-terminus is required for targeting to SGs 19 , suggesting that the intrinsic propensity of the TDP-43 C-terminus to aggregate might be intimately involved in ROS-related pathogenesis.…”

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confidence: 99%

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Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

et al. 2013

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Conformational disorders are involved in various neurodegenerative diseases. Reactive oxygen species (ROS) are the major contributors to neurodegenerative disease; however, ROS that affect the structural changes in misfolded disease proteins have yet to be well characterized. Here we demonstrate that the intrinsic propensity of TDP-43 to aggregate drives the assembly of TDP-43-positive stress granules and soluble toxic TDP-43 oligomers in response to a ROS insult via a disulfide crosslinking-independent mechanism. Notably, ROS-induced TDP-43 protein assembly correlates with the dynamics of certain TDP-43-associated chaperones. The heat-shock protein (HSP)-90 inhibitor 17-AAG prevents ROS-induced TDP-43 aggregation, alters the type of TDP-43 multimers and reduces the severity of pathological TDP-43 inclusions. In summary, our study suggests that a common mechanism could be involved in the pathogenesis of conformational diseases that result from HSP dysregulation.

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“…TDP-43 comprises an N-terminal domain (TDP-43 NTD ), two RNA recognition motif single-stranded nucleic acid binding domains, and a disordered C-terminal domain (TDP-43 CTD ) 5 . The glycine rich C-terminal domain, which harbors the vast majority of disease-linked mutations 4 , selfinteracts and undergoes both liquid-liquid phase separation and aggregation [6][7][8] . While none of the hitherto identified pathogenic mutations reside within the N-terminal domain, recent in vivo studies clearly indicate a role for the N-terminal domain in pathogenic aggregation 3,9,10 .…”

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confidence: 99%

The N-terminal domain of ALS-linked TDP-43 assembles without misfolding

Tsoi

Choi

Leonard

et al. 2017

Preprint

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TDP-43 forms inclusions in several neurodegenerative diseases, and both its N- and C-terminal domains are implicated in this process. We show that the folded TDP-43 N-terminal domain oligomerizes under physiological conditions and propose that, in full-length TDP-43, association between folded N-terminal domains enhances the propensity of the intrinsically unfolded C-terminal domains to drive pathological aggregation.

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The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

Cited by 76 publications

References 50 publications

Self-assembled FUS binds active chromatin and regulates gene transcription

Self-assembled FUS binds active chromatin and regulates gene transcription

Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

The N-terminal domain of ALS-linked TDP-43 assembles without misfolding

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