Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

D'Amico, Francesca; Mukhopadhyay, Rishov; Ovaa, Huib; Mulder, Monique P. C.

doi:10.1002/cbic.202000787

Cited by 21 publications

(21 citation statements)

References 227 publications

(262 reference statements)

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“…Of these, the RING domain exhibits E3 ubiquitin ligase activity, whereas the B-box and curly helix domain mediate protein-protein interactions [20]. Members of the TRIM family are involved in various biological processes including cell cycle regulation, autophagy, antiviral immunity, tumorigenesis, and tumor progression [21]. TRIM22 expression may be induced by interferon and its 5′ anking region gene contains two homologous sequences of IFN-stimulated response elements, which bind to IFN regulatory factor 1 in response to types I and II IFN stimulation and induce TRIM22 expression [22].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of autophagy induced by activation of the AMPK/ERK/mTOR signaling pathway after TRIM22-mediated DENV-2 infection of HUVECs

Gou

et al. 2022

Preprint

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Background Dengue virus type 2 (DENV-2) was used to infect primary human umbilical vein endothelial cells (HUVECs) to examine autophagy induced by activation of the adenosine monophosphate-activated protein kinase (AMPK)/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR) signaling pathway following tripartite motif-containing 22 (TRIM22)-mediated DENV-2 infection to further reveal the underlying pathogenic mechanism of DENV-2 infection. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to screen putative interference targets of TRIM22 and determine the knockdown efficiency. The effect of TRIM22 knockdown on HUVEC proliferation was determined using the CCK8 assay. Following TRIM22 knockdown, transmission electron microscopy (TEM) was used to determine the ultrastructure of HUVEC autophagosomes and expression of HUVEC autophagy and AMPK pathway-related genes were measured by qRT-PCR. Moreover, HUVEC autophagy and AMPK pathway-related protein expression levels were determined by western blot analysis. Cell cycle and apoptosis were assessed by flow cytometry (FCM) and the autophagosome structure of the HUVECs was observed by TEM. Results Western blot results indicated that TRIM22 protein expression levels increased significantly 36 h after DENV-2 infection, which was consistent with the proteomics prediction. The CCK8 assay revealed that HUVEC proliferation was reduced following TRIM22 knockdown (P < 0.001). The TEM results indicated that HUVEC autolysosomes increased and autophagy was inhibited after TRIM22 knockdown. The qRT-PCR results revealed that after TRIM22 knockdown, the expression levels of antithymocyte globulin 7 (ATG7), antithymocyte globulin 5 (ATG5), Beclin1, ERK, and mTOR genes decreased (P < 0.01); however, the expression of AMPK genes (P < 0.05) and P62 genes (P < 0.001) increased. FCM revealed that following TRIM22 knockdown, the percentage of HUVECs in the G2 phase increased (P < 0.001) along with cell apoptosis. The effect of TRIM22 overexpression on HUVEC autophagy induced by DENV-2 infection and AMPK pathways decreased after adding an autophagy inhibitor. Conclusions In HUVECs, TRIM22 protein positively regulates autophagy and may affect autophagy through the AMPK/ERK/mTOR signaling pathway. Autophagy is induced by activation of the AMPK/ERK/mTOR signaling pathway following TRIM22-mediated DENV-2 infection of HUVECs.

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Section: Discussionmentioning

confidence: 99%

Mechanism of autophagy induced by activation of the AMPK/ERK/mTOR signaling pathway after TRIM22-mediated DENV-2 infection of HUVECs

Gou

et al. 2022

Preprint

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“…Therefore, key deubiquitinases and E3 ubiquitin-ligases are promising therapeutic targets for the prevention of neurodegeneration [ 35 ]. In particular, TRIM proteins, which represent one of the largest classes of RING-containing E3 ubiquitin-ligases, are potentially druggable [ 36 ].…”

Section: Team Workmentioning

confidence: 99%

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network

et al. 2022

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Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.

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“…In this method, antibodies are introduced to a target protein, and then TRIM21 is recruited by the antibody bound target protein followed by the proteasome-mediated degradation of the target protein and antibody-bound TRIM21 complex [ 67 ]. Although it is yet to be explored, there is immense opportunity for developing new drugs using TRIMs in many other ways like targeting the substrate binding domains (e.g., PRY/SPRY, NHL), exploiting the homo/hetero-typic interactions among TRIMs, and the possibility of interfering in the catalytic activation paths of TRIMs’ E3 ligase activity [ 68 , 69 , 70 ]. At the same time, there are also some major reasons that have slowed the pace of TRIM family proteins to enter the pharmaceutical industry.…”

Section: E3 Ligases In the Post ‘Genomic Bubble’ Burst Scenario: Industrial And Entrepreneurial Landscapementioning

confidence: 99%

Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

Bhaduri

Merla

2021

Cells

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Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

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Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

Cited by 21 publications

References 227 publications

Mechanism of autophagy induced by activation of the AMPK/ERK/mTOR signaling pathway after TRIM22-mediated DENV-2 infection of HUVECs

Mechanism of autophagy induced by activation of the AMPK/ERK/mTOR signaling pathway after TRIM22-mediated DENV-2 infection of HUVECs

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network

Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

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