TRIM21 and the Function of Antibodies inside Cells

Rhodes, David A.; Isenberg, David

doi:10.1016/j.it.2017.07.005

Cited by 74 publications

(76 citation statements)

References 111 publications

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“…For example, PB10 and SylH3 each bind to ricin with subnanomolar affinities and would be expected to stay associated with ricin following endocytosis, whereas mannan has only micromolar affinity for the MR and would be expected to serve as a relatively weak competitive inhibitor, even at saturating doses. However, the story could be more complicated if the ricin–MAb complexes are delivered into the cytosol where actors like TRIM‐21 are able to promote the clearance of IgG‐based immune complexes …”

Section: Resultsmentioning

confidence: 99%

Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Mooney

Torres-Vélez

Doering

et al. 2019

Journal of Leukocyte Biology

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Ricin toxin is a plant‐derived, ribosome‐inactivating protein that is rapidly cleared from circulation by Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs)—with fatal consequences. Rather than being inactivated, ricin evades normal degradative pathways and kills both KCs and LSECs with remarkable efficiency. Uptake of ricin by these 2 specialized cell types in the liver occurs by 2 parallel routes: a “lactose‐sensitive” pathway mediated by ricin's galactose/N‐acetylgalactosamine‐specific lectin subunit (RTB), and a “mannose‐sensitive” pathway mediated by the mannose receptor (MR; CD206) or other C‐type lectins capable of recognizing the mannose‐side chains displayed on ricin's A (RTA) and B subunits. In this report, we investigated the capacity of a collection of ricin‐specific mouse MAb and camelid single‐domain (VHH) antibodies to protect KCs and LSECs from ricin‐induced killing. In the case of KCs, individual MAbs against RTA or RTB afforded near complete protection against ricin in ex vivo and in vivo challenge studies. In contrast, individual MAbs or VHHs afforded little (<40%) or even no protection to LSECs against ricin‐induced death. Complete protection of LSECs was only achieved with MAb or VHH cocktails, with the most effective mixtures targeting RTA and RTB simultaneously. Although the exact mechanisms of protection of LSECs remain unknown, evidence indicates that the Ab cocktails exert their effects on the mannose‐sensitive uptake pathway without the need for Fcγ receptor involvement. In addition to advancing our understanding of how toxins and small immune complexes are processed by KCs and LSECs, our study has important implications for the development of Ab‐based therapies designed to prevent or treat ricin exposure should the toxin be weaponized.

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Section: Resultsmentioning

confidence: 99%

Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Mooney

Torres-Vélez

Doering

et al. 2019

Journal of Leukocyte Biology

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“…S100A10, a small dimeric helix-loop-helix protein residing in a tight complex with Annexin A2, appeared to regulate the intracellular trafficking of a variety of membrane-resident proteins, such as cathepsin B (38). TRIM21 is an E3 ubiquitin ligase associated with autoimmune diseases (39), and the dysregulation of TRIM21 facilitates human cancer development (40,41). This study detected a significant decrease of TRIM21 and Annexin A2 levels in PGCCs with their daughter cells after S100A4 knockdown as well as a reduced nuclear translocation of S100A10 in daughter cells, while 14-3-3 ζ/δ and Ezrin did not vary.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.

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“…Tripartite motif-containing protein 21 (TRIM21) was detected in iBECs ( Supplementary Fig. S1), but it is known to mediate the ubiquitination of IgG-antigen complexes 39 and no reports suggest it contributes to IgG transcytosis. The expression of TRIM21 remains to be confirmed in vivo, but it may be the unidentified IgG-associated protein previously reported in BECs because of its comparable MW 12 .…”

Section: Discussionmentioning

confidence: 99%

Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn

Ruano-Salguero

Lee

2020

Sci Rep

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The blood-brain barrier (BBB) hinders the brain delivery of therapeutic immunoglobulin γ (igG) antibodies. Evidence suggests that IgG-specific processing occurs within the endothelium of the BBB, but any influence on transcytosis remains unclear. Here, involvement of the neonatal Fc receptor (FcRn), which mediates IgG recycling and transcytosis in peripheral endothelium, was investigated by evaluating the transcytosis of IgGs with native or reduced FcRn engagement across human induced pluripotent stem cell-derived brain endothelial-like cells. Despite differential trafficking, the permeability of all tested IgGs were comparable and remained constant irrespective of concentration or competition with excess IgG, suggesting IgG transcytosis occurs nonspecifically and originates from fluid-phase endocytosis. Comparison with the receptor-enhanced permeability of transferrin indicates that the phenomena observed for IgG is ubiquitous for most macromolecules. However, increased permeability was observed for macromolecules with biophysical properties known to engage alternative endocytosis mechanisms, highlighting the importance of biophysical characterizations in assessing transcytosis mechanisms.The brain endothelial cells (BECs) that form the main structural component of the blood-brain barrier (BBB) are central to the protection of brain parenchyma. Unique from peripheral endothelium, BECs exhibit substantially reduced permeability of most bloodborne molecules 1 . Accordingly, this restrictive physiology also poses a formidable obstacle in the brain delivery of therapeutic molecules 2 . In particular, conventional immunoglobulin γ (IgG) antibody-based passive immunotherapies, which are structurally and functionally similar to endogenous IgGs, only demonstrate brain uptake of 0.1-0.3% of the injected dose 3,4 . Despite the need to improve the brain delivery of conventional therapeutic IgGs 5 , progress is hindered by the current lack of understanding regarding their interactions with BECs.IgG-endothelium interactions in the periphery are dominated by the neonatal fragment crystallizable (Fc) receptor (FcRn). Following internalization of circulating IgG, the acidic microenvironment of endosomal compartments enables FcRn to bind and recycle IgG back to the lumen in a pH-dependent manner 6 . FcRn-mediated recycling therefore limits lysosomal degradation and contributes to the extended serum half-life of IgGs. However, FcRn can also mediate the abluminal transcytosis of IgG, which is exemplified in the transfer of maternal IgG across the placental endothelium. In this regard, FcRn is a unique transcytosis receptor, e.g. compared to the transferrin receptor (TfR) 7 , as it can shuttle its ligand bidirectionally to either cell surface (i.e. luminal recycling or abluminal transcytosis) 8 . Traditional transcytosis pathways are categorized as fluid-phase (e.g. macropinocytosis) or adsorptive-mediated, which occur via specific (e.g. receptor-mediated transcytosis (RMT)) or nonspecific (e.g. electrostatic adsorption) processes....

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TRIM21 and the Function of Antibodies inside Cells

Cited by 74 publications

References 111 publications

Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn

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