Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression

Tsytsykova, Alla V.; Wiley, Graham B.; Li, Chuang; Pelikan, Richard; Garman, Lori; Acquah, Francis A.; Mooers, Blaine H. M.; Tsitsikov, Erdyni; Dunn, Ian F.

doi:10.1016/j.isci.2022.104839

Cited by 5 publications

(5 citation statements)

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“…For example, TRAF7 has been shown to both promote or inhibit inflammation(16) by either activating(18, 20) or inhibiting(28) the NF-kB signaling pathway. Additionally, TRAF7-dependent ubiquitination can inhibit type I IFN signaling(38, 39) and promote epithelial-mesenchymal transition (EMT)(41), a reprogramming event that is induced by C. trachomatis infection(42). Thus, further study of the consequences of the Tri1:TRAF7 interaction may provide new insights into TRAF7 modulation of these important signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

TheChlamydia trachomatisInc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners

Herrera,

McMahon,

Swaney

et al. 2024

Preprint

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Chlamydia trachomatisis the leading cause of bacterial sexually transmitted infections in the US and of preventable blindness worldwide. This obligate intracellular pathogen replicates within a membrane-bound inclusion, but how it acquires nutrients from the host while avoiding detection by the innate immune system is incompletely understood.C. trachomatisaccomplishes this in part through the translocation of a unique set of effectors into the inclusion membrane, theinclusion membrane proteins (Incs). Incs are ideally positioned at the host-pathogen interface to reprogram host signaling by redirecting proteins or organelles to the inclusion. Using a combination of co-affinity purification, immunofluorescence confocal imaging, and proteomics, we characterize the interaction between an early-expressed Inc of unknown function, Tri1, and tumor necrosis factor receptor associated factor 7 (TRAF7). TRAF7 is a multi-domain protein with a RING finger ubiquitin ligase domain and a C-terminal WD40 domain. TRAF7 regulates several innate immune signaling pathways associated withC. trachomatisinfection and is mutated in a subset of tumors. We demonstrate that Tri1 and TRAF7 specifically interact during infection and that TRAF7 is recruited to the inclusion. We further show that the predicted coiled-coil domain of Tri1 is necessary to interact with the TRAF7 WD40 domain. Finally, we demonstrate that Tri1 displaces the native TRAF7 binding partners, mitogen activated protein kinase kinase kinase 2 (MEKK2) and MEKK3. Together, our results suggest that by displacing TRAF7 native binding partners, Tri1 has the capacity to alter TRAF7 signaling duringC. trachomatisinfection.ImportanceChlamydia trachomatisis the leading cause of bacterial sexually transmitted infections in the US and preventable blindness worldwide. Although easily treated with antibiotics, the vast majority of infections are asymptomatic and therefore go untreated, leading to infertility and blindness. This obligate intracellular pathogen evades the immune response, which contributes to these outcomes. Here, we characterize the interaction between aC. trachomatissecreted effector, Tri1, and a host protein involved in innate immune signaling, TRAF7. We identified host proteins that bind to TRAF7 and demonstrate that Tri1 can displace these proteins upon binding to TRAF7. Remarkably, the region of TRAF7 to which these host proteins bind is often mutated in a subset of human tumors. Our work suggests a mechanism by which Tri1 may alter TRAF7 signaling and has implications not only in the pathogenesis ofC. trachomatisinfections, but also in understanding the role of TRAF7 in cancer.

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Section: Discussionmentioning

confidence: 99%

TheChlamydia trachomatisInc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners

Herrera,

McMahon,

Swaney

et al. 2024

Preprint

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“…In our cohort, patent ductus arteriosus was the most prevalent manifestation together with a combination of severe cardiac, valvular and vessel pathologies including life-threatening abnormalities such as hypoplastic aortic arch leading to cardiac insufficiency in four patients in the cases presented here. The involvement of TRAF7 in endothelial tissues, and particularly regarding vascular complications, has been recently demonstrated in a murine model [14].…”

Section: Discussionmentioning

confidence: 99%

“…All of them share a domain organization consisting of a modular structure, which allows them to convey signals from different receptors, but each plays a unique and well-defined role in cellular biology. Specifically, TRAF7 is a multifunctional intracellular protein that acts as a key mediator of the nuclear factor-κB (NF-κB), the mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinase (ERK) signaling pathways, playing a crucial role in the control of cell survival, apoptosis, proliferation, and differentiation [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review

Palma-Milla,

Prat-Planas,

Soengas-Gonda

et al. 2023

Preprint

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TRAF7 syndrome, a multisystemic neurodevelopmental disorder caused by germline missense variants in theTRAF7gene, exhibits heterogeneous clinical presentations. We present a detailed description of eleven new TRAF7 syndrome cases, featuring eight distinct variants, including a novel one. Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germlineTRAF7variants and somatic changes linked to meningiomas. Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7 syndrome, offering insights for improved diagnosis, intervention, and patient care.Key MessageTRAF7 syndrome, a complex neurodevelopmental disorder, exhibits variable cognitive outcomes, complex behavioral presentation and clinical complications emphasizing the need for tailored interventions and follow-up.

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“…KLF4-K409Q mutations are found in a subset of NF2 wild-type meningiomas and almost always cooccur with mutations in TRAF7. The K409Q mutation lies in the first zinc finger of the KLF4 DNA-binding domain, and the lysine residue in this position is conserved between all members of the Sp/KLF superfamily ( 37 ). The exact impact of this mutation remains unknown, and both gain- and loss-of-function effects have been reported.…”

Section: Frequent Genomic Aberrations In Meningiomamentioning

confidence: 99%

“…Tsytsykova et al reported that the K409Q mutation alters the DNA recognition preference of KLF4, resulting in a shift in downstream transcriptional activity. Among other targets, this leads to the transcriptional activation of fibroblast growth factor 3 (FGF3) expression in KLF4-K409Q-expressing cells, not present in wild-type KLF4-expressing cells, and KLF4-K409Q-mutated meningiomas expressed higher levels of FGF3 compared to KLF4-wild-type tumors ( 37 ). Furthermore, KLF4-K409Q-expressing meningioma cells show high levels of PI3K-AKT-mTOR pathway activation and respond to mTOR inhibitors ( 38 ).…”

Section: Frequent Genomic Aberrations In Meningiomamentioning

confidence: 99%

Meningioma: current updates on genetics, classification, and mouse modeling

Szulzewsky,

Thirimanne,

Holland

2024

ujms

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Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well as brain invasion, and often recurs even after several rounds of surgery. Increasing evidence suggests that tumor classification and grading primarily based on histopathology do not always accurately predict tumor aggressiveness and recurrence behavior. The underlying biology of aggressive treatment-resistant meningiomas and the impact of specific genetic aberrations present in these high-grade tumors is still only insufficiently understood. Therefore, an in-depth research into the biology of this tumor type is warranted. More recent studies based on large-scale molecular data such as whole exome/genome sequencing, DNA methylation sequencing, and RNA sequencing have provided new insights into the biology of meningiomas and have revealed new risk factors and prognostic subtypes. The most common genetic aberration in meningiomas is functional loss of NF2 and occurs in both low- and high-grade meningiomas, whereas NF2-wildtype meningiomas are enriched for recurrent mutations in TRAF7, KLF4, AKT1, PI3KCA, and SMO and are more frequently benign. Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.

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Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression

Cited by 5 publications

References 84 publications

TheChlamydia trachomatisInc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners

TheChlamydia trachomatisInc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners

Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review

Meningioma: current updates on genetics, classification, and mouse modeling

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