Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

Schreiber, Joerg; Végh, Marlene J.; Dawitz, Julia; Kroon, Tim; Loos, Maarten; Labonté, Dorthe; Li, Ka Wan; Nierop, Pim van; Diepen, Michiel van; Zeeuw, Chris I. De; Kneussel, Matthias; Meredith, Rhiannon M.; Smit, August B.; Kesteren, Ronald E. van

doi:10.1084/jem.21212oia103

Cited by 6 publications

(13 citation statements)

References 49 publications

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“…The UPS targets proteins for proteolysis through the conjugation of ubiquitin to substrates, which is coordinated by E3s (16). INO80 was previously identified as a substrate of TRIM3, an E3 that has been implicated in hippocampal synaptic plasticity and memory (21). Following extendedaccess cocaine self-administration, we found a decrease in TRIM3 protein expression in NAc P1 fractions on AD30 (Fig.…”

Section: Proteasomal Degradation Of Ino80 In the Nac Is Decreased Dur...mentioning

confidence: 65%

“…Furthermore, viral-mediated manipulation of INO80 bidirectionally mediated the expression of cocaine craving on AD30. We then examined E3 ubiquitin ligase (E3) tripartite motif-containing protein 3 (TRIM3), of which INO80 is a substrate (21). We found that TRIM3 protein expression and interaction with INO80 are decreased on AD30, indicating that the ubiquitin-proteasomal regulation of INO80 is impaired during prolonged abstinence from cocaine.…”

Section: Introductionmentioning

confidence: 99%

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Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving

et al. 2019

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Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies (“incubates”) during abstinence and is believed to contribute to persistent relapse vulnerability. Changes in gene expression often govern perpetual behavioral abnormalities, but epigenetic plasticity during prolonged abstinence from drug exposure is poorly understood. We examined how E3 ubiquitin ligase TRIM3 dysregulates chromatin remodeler INO80 to mediate cocaine craving during prolonged abstinence. We found that INO80 expression increased in the NAc on abstinence day 30 (AD30) but not on AD1 following cocaine self-administration. Furthermore, TRIM3, which mediates degradation of INO80, was reduced on AD30, along with TRIM3-INO80 interaction. Viral-mediated gene transfer of INO80 or TRIM3 governed cocaine craving during prolonged abstinence. Lastly, chromatin immunoprecipitation followed by massively parallel DNA sequencing identified INO80-mediated transcriptional regulation of predicted pathways associated with cocaine plasticity. Together, these results demonstrate a novel ubiquitin-proteasomal-epigenetic mechanism by which TRIM3-INO80 mediates cocaine craving during prolonged abstinence.

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Section: Proteasomal Degradation Of Ino80 In the Nac Is Decreased Dur...mentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving

et al. 2019

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“…For example, in mammals, mass-spectrometry studies found evidence that some of the many actin isoforms are ubiquitinated in vivo (45,46), and some of the putative ubiquitination sites correspond to the lysines that are present in IDA5 but not in NAP1. In addition, a recombinant actin expressed in mouse muscle cells was found to be ubiquitinated and degraded (47), and in synapses, ubiquitination was found to regulate γ-actin levels (48) and thus add an important layer of regulation of the balance of actin isoforms during the establishment of neuronal connections (49,50).…”

Section: Regulation Of Actin Levels By Ubiquitin-proteasome-mediated mentioning

confidence: 99%

F-actin homeostasis through transcriptional regulation and proteasome-mediated proteolysis

Onishi

Pecani

Jones

et al. 2018

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

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Many organisms possess multiple and often divergent actins whose regulation and roles are not understood in detail. For example, has both a conventional actin (IDA5) and a highly divergent one (NAP1); only IDA5 is expressed in normal proliferating cells. We showed previously that the drug latrunculin B (LatB) causes loss of filamentous (F-) IDA5 and strong up-regulation of NAP1, which then provides essential actin function(s) by forming LatB-resistant F-NAP1. RNA-sequencing analyses now show that this up-regulation of NAP1 reflects a broad transcriptional response, much of which depends on three proteins (LAT1, LAT2, and LAT3) identified previously as essential for transcription. Many of the LAT-regulated genes contain a putative -acting regulatory site, the "LRE motif." The LatB transcriptional program appears to be activated by loss of F-IDA5 and deactivated by formation of F-NAP1, thus forming an F-actin-dependent negative-feedback loop. Multiple genes encoding proteins of the ubiquitin-proteasome system are among those induced by LatB, resulting in rapid degradation of IDA5 (but not NAP1). Our results suggest that IDA5 degradation is functionally important because nonpolymerizable LatB-bound IDA5 interferes with the formation of F-NAP1. The genes for the actin-interacting proteins cofilin and profilin are also induced. Cofilin induction may further the clearance of IDA5 by promoting the scission of F-IDA5, whereas profilin appears to function in protecting monomeric IDA5 from degradation. This multifaceted regulatory system allows rapid and quantitative turnover of F-actin in response to cytoskeletal perturbations and probably also maintains F-actin homeostasis under normal growth conditions.

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“…TRIM3 belongs to the tripartite motif (TRIM) family, which is also called the 'RING-B-box-coiled-coil' (RBCC) subgroup of RING finger proteins. As an ubiquitin ligase, TRIM3 participates in critical physiological processes such as hippocampal plasticity and learning by modulating protein degradation (Hung et al 2010;Schreiber et al 2015). Interestingly, the protein level of TRIM3 was upregulated in non-small cell lung cancer (NSCLC) cell lines, however its expression in human specimens and clinical significance need further investigation (Zhan et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Tripartite Motif Containing 3 inhibits the aggressive behaviors of papillary thyroid carcinoma and indicates lower recurrence risk

et al. 2021

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Background Tripartite Motif Containing 3 (TRIM3) has been reported to be downregulated in several malignancies. However, its prognostic significance in thyroid cancer remains unknown. Objective Here we aimed to investigate TRIM3's expression and its involvement in papillary thyroid carcinoma (PTC). Methods Clinicopathological analyses were performed in patients with PTC. Expression of TRIM3 protein was evaluated by IHC. The prognostic role of TRIM3 in PTC patients was assessed by univariate and multivariate analyses. Cell proliferation and invasion were tested in two PTC cell lines following overexpression or knockdown. Results TRIM3 was decreased in PTC tissues compared to adjacent thyroid tissues on both mRNA and protein levels. Additionally, low expression of TRIM3 was significantly related to tumor size, lymph node metastasis and TNM stage. Moreover, TRIM3 was identified as an independent prognosis factor by multivariate analysis. Cellular data revealed that TRIM3 can inhibit the proliferation and invasion of PTC cells. Consistently, TRIM3 can upregulate the expression level of E-cadherin, while downregulate N-cadherin, Vimentin, and cyclin D1 expression. Conclusions TRIM3 expression was downregulated in PTC tissues comparing with that in adjacent nontumorous thyroid tissues. Lower TRIM3 expression in PTC can contribute independently to a poorer prognosis by enhancing PTC proliferation and invasion, highlighting its potential as a novel therapeutic target and prognostic biomarker.

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Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

Cited by 6 publications

References 49 publications

Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving

Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving

F-actin homeostasis through transcriptional regulation and proteasome-mediated proteolysis

Tripartite Motif Containing 3 inhibits the aggressive behaviors of papillary thyroid carcinoma and indicates lower recurrence risk

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