TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase

Urano, Tomohiko; Usui, Takahiko; Takeda, Satomi; Ikeda, Kazuhiro; Okada, Atsushi; Ishida, Yoshiko; Iwayanagi, Takao; Otomo, Jun; Ouchi, Yasuyoshi; Inoue, Satoshi

doi:10.1016/j.bbrc.2009.04.010

Cited by 52 publications

(70 citation statements)

References 22 publications

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“…We found that the inhibitory activities of TRIM17 extended to blocking precision autophagy mediated by other TRIMs, as exemplified by its ability to prevent TRIM5α-dependent degradation of HIV-1 capsids. In addition to the interactions between TRIM17 and several TRIMs (TRIM5α and TRIM22) shown here, TRIM17 has also been reported to interact with TRIM44 (Urano et al, 2009). TRIM17 binding to other TRIM family members could similarly interfere with their proautophagy functions, thus protecting their cognate substrates from degradation and extending the substrate-protective repertoire of TRIM17.…”

Section: Discussionmentioning

confidence: 53%

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Mandell

Jain

Kumar

et al. 2016

Journal of Cell Science

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TRIM proteins contribute to selective autophagy, a process whereby cells target specific cargo for autophagic degradation. In a previously reported screen, TRIM17 acted as a prominent inhibitor of bulk autophagy, unlike the majority of TRIMs, which had positive roles. Nevertheless, TRIM17 showed biochemical hallmarks of autophagyinducing TRIMs. To explain this paradox, here, we investigated how TRIM17 inhibits selective autophagic degradation of a subset of targets while promoting degradation of others. We traced the inhibitory function of TRIM17 to its actions on the anti-autophagy protein Mcl-1, which associates with and inactivates Beclin 1. TRIM17 expression stabilized Mcl-1-Beclin-1 complexes. Despite its ability to inhibit certain types of selective autophagy, TRIM17 promoted the removal of midbodies, remnants of the cell division machinery that are known autophagy targets. The selective loss of anti-autophagy Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlated with the ability of TRIM17 to promote midbody removal. This study further expands the roles of TRIMs in regulating selective autophagy by showing that a single TRIM can, depending upon a target, either positively or negatively regulate autophagy.

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Section: Discussionmentioning

confidence: 53%

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Mandell

Jain

Kumar

et al. 2016

Journal of Cell Science

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“…33,34 We and others have demonstrated that Trim17 is a bona fide E3 ubiquitin-ligase. 25,35 In addition, we have shown that the E3 activity of Trim17 is both necessary and sufficient for the initiation of neuronal apoptosis. 25 Recently, human TRIM17 has been found to stimulate the proteasome-dependent degradation of the kinetochore protein ZWINT.…”

Section: Discussionmentioning

confidence: 91%

“…High levels of Trim17 mRNA have been detected not only in apoptotic neurons 25 but also in organs with a high rate of apoptosis such as testis, spleen and thymus. 35 Future work will determine whether Trim17 can mediate the degradation of Mcl-1 and control the initiation of apoptosis in non-neuronal cells. As Mcl-1 is a major anti-apoptotic protein, the activities that regulate its protein level are potentially important in many physiological and pathological situations.…”

Section: Discussionmentioning

confidence: 99%

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

et al. 2012

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Short-term proteasome inhibition has been shown to prevent neuronal apoptosis. However, the key pro-survival proteins that must be degraded for triggering neuronal death are mostly unknown. Here, we show that Mcl-1, an anti-apoptotic Bcl-2 family member, is degraded by the proteasome during neuronal apoptosis. Using primary cultures of cerebellar granule neurons deprived of serum and KCl, we found that ubiquitination and proteasomal degradation of Mcl-1 depended on its prior phosphorylation by GSK3, providing the first insight into post-translational regulation of Mcl-1 in neurons. In a previous study, we have reported that the E3 ubiquitin-ligase Trim17 is both necessary and sufficient for neuronal apoptosis. Here, we identified In the nervous system, apoptosis plays a critical role both during development and in neurodegenerative diseases. 1 In many neuronal types, apoptosis is triggered through the intrinsic pathway of caspase activation that involves the release of cytochrome c from mitochondria. The proteins of the Bcl-2 family, that comprises both anti-apoptotic (Bcl-2, Bcl-x L , Mcl-1y) and pro-apoptotic members (Bax, Bak, Bimy), play an essential role in the regulation of apoptosis by controlling the integrity of the outer mitochondrial membrane and the release of apoptogenic factors such as cytochrome c. 2 Amongst the anti-apoptotic proteins of the Bcl-2 family, Mcl-1 (Myeloid cell leukemia 1) is characterized by a short half-life. 3 Its rapid degradation by the proteasome has been shown to be required for initiation of the apoptotic cascade in several cell lines. [4][5][6][7] For a long time, little attention was paid to a potential role for Mcl-1 in the nervous system because initial studies did not detect it in neurons. However, Mcl-1 is expressed in cerebellar granule neurons (CGNs) in vivo, 8 and Mcl-1 expression has been associated with neuroprotection in the hippocampus. 9 More recently, elegant studies using different conditional Mcl-1 mouse mutants, showed that Mcl-1 is required for neuronal development, that loss of Mcl-1 sensitizes neurons to DNA damage-induced apoptosis and that Mcl-1 negatively regulates autophagy in starved neurons. 10,11 Therefore, Mcl-1 appears to play a crucial role in neuronal survival. Nevertheless, post-translational regulation of Mcl-1 has never been studied in neurons.In the present study, we report for the first time that Mcl-1 is degraded by the proteasome during neuronal apoptosis. We found that Mcl-1 degradation depended on its prior phosphorylation by glycogen synthase kinase 3 (GSK3), in primary cultures of CGNs deprived of serum and KCl. This phosphorylation of Mcl-1 favored its physical interaction with Trim17, a novel E3 ubiquitin-ligase involved in neuronal apoptosis. Moreover, our present data provide evidence that Trim17 contributes to the ubiquitination and the proteasomal degradation of Mcl-1 in neurons. As such, we define a novel molecular mechanism for regulation of Mcl-1 and initiation of apoptosis. ResultsMcl-1 is degraded by the proteasome during...

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“…As Trim17 is an E3 ubiquitin ligase, 25,29,30 we examined whether Trim17 could mediate NFATc3 ubiquitination. Unexpectedly, the protein level of NFATc3 progressively increased when co-transfected with increasing amounts of Trim17 in Neuro2A cells (Supplementary Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

et al. 2014

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Neuronal apoptosis induced by survival factor deprivation is strongly regulated at the transcriptional level. Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the control of the survival/death fate of neurons. However, the mechanisms that regulate NFAT activity in response to apoptotic stimuli and the target genes that mediate their effect on neuronal apoptosis are mostly unknown. In a previous study, we identified Trim17 as a crucial E3 ubiquitin ligase that is necessary and sufficient for neuronal apoptosis. Here, we show that Trim17 binds preferentially SUMOylated forms of NFATc3. Nonetheless, Trim17 does not promote the ubiquitination/degradation of NFATc3. NFAT transcription factors are regulated by calcium/calcineurin-dependent nuclear-cytoplasmic shuttling. Interestingly, Trim17 reduced by twofold the calcium-mediated nuclear localization of NFATc3 and, consistent with this, halved NFATc3 activity, as estimated by luciferase assays and by measurement of target gene expression. Trim17 also inhibited NFATc4 nuclear translocation and activity. NFATc4 is known to induce the expression of survival factors and, as expected, overexpression of NFATc4 protected cerebellar granule neurons from serum/KCl deprivation-induced apoptosis. Inhibition of NFATc4 by Trim17 may thus partially mediate the proapoptotic effect of Trim17. In contrast, overexpression of NFATc3 aggravated neuronal death, whereas knockdown of NFATc3 protected neurons from apoptosis. This proapoptotic effect of NFATc3 might be due to a feedback loop in which NFATc3, but not NFATc4, induces the transcription of the proapoptotic gene Trim17. Indeed, we found that overexpression or silencing of NFATc3, respectively, increased or decreased Trim17 levels, whereas NFATc4 had no significant effect on Trim17 expression. Moreover, we showed that NFATc3 binds to the promoter of the Trim17 gene together with c-Jun. Therefore, our results describe a novel mechanism regulating NFAT transcription factors beyond the calcium/calcineurin-dependent pathway and provide a possible explanation for the opposite effects of NFATc3 and NFATc4 on neuronal apoptosis.

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TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase

Cited by 52 publications

References 22 publications

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

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