TRIM67 regulates exocytic mode and neuronal morphogenesis via SNAP47

Urbina, Fabio; Menon, Shalini; Goldfarb, Dennis; Edwards, Reginald James; Major, Michael B.; Brennwald, Patrick; Gupton, Stephanie L.

doi:10.1016/j.celrep.2021.108743

Cited by 16 publications

(16 citation statements)

References 81 publications

(143 reference statements)

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“…SNARE-mediated fusion is an essential mechanism that drives the synaptic transmission, neuron development, and growth. SNAP47 plays a role in exocytic mode and neuronal morphogenesis ( Holt et al., 2006 ; Urbina et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Boer¹,

Hatzikotoulas²,

Southam³

et al. 2021

Cell

268

159

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Summary Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

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Section: Resultsmentioning

confidence: 99%

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Boer¹,

Hatzikotoulas²,

Southam³

et al. 2021

Cell

268

159

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“…Our results indicate that TRIM67 acts as an oncogene through the activation of Rho GTPase signaling-dependent membrane blebbing mechanism, leading to cell motility and tumor progression. Our findings illustrate a crucial oncogenic role of TRIM67 in gliomas apart from its essential biological roles in neural development, axon guidance, filopodia dynamics, exocytosis and synaptic vesicle formation (4,(6)(7)(8) In this context, our findings bring a novel player into the glioma biology, which appears to have essential consequences for oligodendroglioma progression. TRIM67 has been shown to have a dichotomous role in different cancers.…”

Section: Discussionmentioning

confidence: 65%

“…Next, we tested the interaction of TRIM67 with TRIM9, the TRIM family member with the closest sequence homology to TRIM67. Both proteins were previously found to associate with cytoskeleton (8), regulate filopodia extensions (6) and play essential roles in axon branching and synaptic vesicle formation (7). By western blotting, we detected a substantial increase in TRIM9 protein levels in three different cell lines (Supplemental Fig.…”

Section: Ectopic Trim67 Expression Induces the Formation Of Membrane Blebsmentioning

confidence: 60%

“…Further evidence suggests that it antagonizes TRIM9-dependent degradation of VASP, positively regulating filopodia extension and axon branching (6). Most recently, TRIM67 and TRIM9 have been suggested to associate with cytoskeletal proteins and synaptic regulators thus playing a role in exocytosis and endocytosis (7,8). Therefore, the recently discovered ubiquitin players of neurogenesis, including TRIM67 and TRIM9, may play a role in neuronal development, degeneration, or tumorigenesis (5,9).…”

Section: Introductionmentioning

confidence: 99%

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TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing

Demirdizen

Al‐Ali

Narayanan

et al. 2021

Preprint

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Oligodendrogliomas are a subtype of isocitrate dehydrogenase (IDH) mutant gliomas defined by the co-deletion of chromosome arms 1p and 19q. Although the somatic genomic alterations of oligodendrogliomas have been well described, transcriptional changes unique to these tumors are not well studied. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas. We characterize the function of TRIM67 using high throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS) and co-immunoprecipitation (IP)-MS using human neural progenitor cells and patient-derived glioma tumorspheres constitutively overexpressing TRIM67. Our high throughput data suggest that TRIM67 overexpression alters the abundance of cytoskeletal proteins, which were validated by functional assays, including immunofluorescence (IF) staining, co-IP and western blotting (WB). Additionally, IF staining results indicate that TRIM67 ectopic expression induces formation of membrane blebs in glioma cells, which could be reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. GTP pulldown and WB assays further indicate that Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression. Phenotypically, TRIM67 expression resulted in higher cell motility in wound healing experiments, reduced cell adherence in adhesion assays, accelerated tumor growth and reduced survival in mouse orthotopic implantation models of an oligodendroglioma-derived patient tumorsphere line. Taken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis.SignificanceWe identify TRIM67 as a novel oncogene in oligodendroglioma that leads to increased cell motility, tumor growth, reduced adhesion, and survival in mice. Our results also show that constitutive TRIM67 expression transforms cell morphology from an adherent to a rounded appearance with membrane blebs. Mechanistic alteration of actin cytoskeleton and Rho GTPase signaling upon TRIM67 upregulation underlies the rounded cell structure and the membrane blebbing phenotype. TRIM67-induced blebbing is specifically regulated by RHOA-RAC1-ROCK2 signaling axis. TRIM67 overexpression also alters pathways associated with cell migration and wound healing in various glioma cell lines and human neural progenitor cells, suggesting a general oncogenic mechanism in gliomas. Overall, our study highlights TRIM67 as a novel player orchestrating cytoskeleton, Rho GTPase signaling and bleb-based cell movement, ultimately causing tumorigenic outcomes in oligodendrogliomas.

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“…Currently, minimal information is known about TRIM67, although it is recognized to be capable of negatively regulating Ras activities by targeting 80K-H for degradation and then triggering neuritogenesis (24). In recent studies, TRIM67 has been reported that it's playing an important role in cancer development (25)(26)(27)(28) and brain development (29)(30)(31)(32). In this study, we performed a microscopic observation to investigate the effects of 22 TRIM proteins on the TNFa-induced nuclear translocation of p65.…”

Section: Introductionmentioning

confidence: 99%

TRIM67 Suppresses TNFalpha-Triggered NF-kB Activation by Competitively Binding Beta-TrCP to IkBa

et al. 2022

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The transcription factor NF-κB plays an important role in modulation of inflammatory pathways, which are associated with inflammatory diseases, neurodegeneration, apoptosis, immune responses, and cancer. Increasing evidence indicates that TRIM proteins are crucial role in the regulation of NF-κB signaling pathways. In this study, we identified TRIM67 as a negative regulator of TNFα-triggered NF-κB activation. Ectopic expression of TRIM67 significantly represses TNFα-induced NF-κB activation and the expression of pro-inflammatory cytokines TNFα and IL-6. In contrast, Trim67 depletion promotes TNFα-induced expression of TNFα, IL-6, and Mcp-1 in primary mouse embryonic fibroblasts. Mechanistically, we found that TRIM67 competitively binding β-transducin repeat-containing protein (β-TrCP) to IκBα results inhibition of β-TrCP-mediated degradation of IκBα, which finally caused inhibition of TNFα-triggered NF-κB activation. In summary, our findings revealed that TRIM67 function as a novel negative regulator of NF-κB signaling pathway, implying TRIM67 might exert an important role in regulation of inflammation disease and pathogen infection caused inflammation.

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TRIM67 regulates exocytic mode and neuronal morphogenesis via SNAP47

Cited by 16 publications

References 81 publications

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing

TRIM67 Suppresses TNFalpha-Triggered NF-kB Activation by Competitively Binding Beta-TrCP to IkBa

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