TRIM21—From Intracellular Immunity to Therapy

Foss, Stian; Bottermann, Maria; Jønsson, Alexandra Brandt Ryborg; Sandlie, Inger; James, Leo C.; Andersen, Jan Terje

doi:10.3389/fimmu.2019.02049

Cited by 106 publications

(93 citation statements)

References 127 publications

(217 reference statements)

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“…It has been found that in mouse and human systems, HAdv-Ab complexes are recognized in the cytosol by cytosolic protein tripartite motif containing-21 (TRIM21), which binds to the Fc portion of the Ab and targets HAdv-Ab complexes for proteasomal degradation [28,29]. An in-depth review of TRIM21dependent neutralization of HAdv-Ab complexes in the cytosol was recently published elsewhere [32]. It should be noted, however, that the TRIM21-dependent mechanism of intracellular degradation of HAdv-Ab complexes does not operate in all cell types.…”

Section: Humoral Factors Affecting Hadv Bio-distribution After Intravmentioning

confidence: 99%

“…Indeed, HAdv mutants unable to bind to coagulation FX could still transduce hepatocytes with very high efficiency after intravenous administration into complement C1q-or C4-deficient mice [26], which have normal levels of circulating natural IgM that form HAdv-Ab immune complexes after intravenous virus administration. An in-depth review of TRIM21dependent neutralization of HAdv-Ab complexes in the cytosol was recently published elsewhere [32].…”

Section: Humoral Factors Affecting Hadv Bio-distribution After Intravmentioning

confidence: 99%

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Innate immunity to adenovirus: lessons from mice

2019

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Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.Human adenovirus (HAdv) is remarkably efficient at infecting and replicating in human cells. These properties made HAdv-based vectors an attractive platform for developing novel therapeutics to combat genetic diseases and cancer. Unfortunately, early studies revealed that HAdv is a potent activator of the innate and adaptive arms of the immune system, and administration to animals or patients of high doses of HAdv-based vectors, especially via an intravascular route, leads to severe immunopathology, manifested by cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which may lead to morbidity and even mortality. To harness the full potential of HAdv as a gene delivery or oncolytic virus platform, a complete understanding of the molecular and cellular components of innate Abbreviations is a founder, shareholder, and chief scientific officer of AdCure Bio, LLC, which develops Ad-based therapies for clinical use.

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Section: Humoral Factors Affecting Hadv Bio-distribution After Intravmentioning

confidence: 99%

Section: Humoral Factors Affecting Hadv Bio-distribution After Intravmentioning

confidence: 99%

Innate immunity to adenovirus: lessons from mice

2019

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“…This review focuses on the cell‐based effector functions that arise from the interaction of IgG with the classical human leukocyte FcγR 7. Although beyond the scope of this review, it should be noted that the IgG‐Fc portion dictates other aspects of an antibody’s biology, including its serum half‐life mediated by the neonatal FcR (FcRn), 3 the activation of complement C1,8 antiviral protection via the intracellular receptor TRIM219 and interactions with the Fc receptor‐like family 10…”

Section: Introductionmentioning

confidence: 99%

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

et al. 2020

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The human fragment crystallizable (Fc)c receptor (R) interacts with antigencomplexed immunoglobulin (Ig)G ligands to both activate and modulate a powerful network of inflammatory host-protective effector functions that are key to the normal physiology of immune resistance to pathogens. More than 100 therapeutic monoclonal antibodies (mAbs) are approved or in late stage clinical trials, many of which harness the potent FccR-mediated effector systems to varying degrees. This is most evident for antibodies targeting cancer cells inducing antibody-dependent killing or phagocytosis but is also true to some degree for the mAbs that neutralize or remove small macromolecules such as cytokines or other Igs. The use of mAb therapeutics has also revealed a "scaffolding" role for FccR which, in different contexts, may either underpin the therapeutic mAb action such as immune agonism or trigger catastrophic adverse effects. The still unmet therapeutic need in many cancers, inflammatory diseases or emerging infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires increased effort on the development of improved and novel mAbs. A more mature appreciation of the immunobiology of individual FccR function and the complexity of the relationships between FccRs and antibodies is fueling efforts to develop more potent "next-gen" therapeutic antibodies. Such development strategies now include focused glycan or protein engineering of the Fc to increase affinity and/or tailor specificity for selective engagement of individual activating FccRs or the inhibitory FccRIIb or alternatively, for the ablation of FccR interaction altogether. This review touches on recent aspects of FccR and IgG immunobiology and its relationship with the present and future actions of therapeutic mAbs.

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“…TRIM21 uses antibodies as intermediary molecules to target a wide-range of substrates for proteasomal degradation including viruses (Fan et al, 2016;Mallery et al, 2010;Vaysburd et al, 2013;Watkinson et al, 2015), bacteria (McEwan et al, 2013;Rakebrandt et al, 2014) and proteopathic agents such as Tau (McEwan et al, 2017). TRIM21 underpins a system of intracellular immunity where the diversity of the body's antibody repertoire can be utilized in the cytosol to degrade invading pathogens (Foss et al, 2019;McEwan et al, 2011). This broad-spectrum targeting capability of TRIM21 has recently been exploited to develop Trim-Away, an easy to use and powerful method for acute and rapid degradation of endogenous cellular proteins.…”

Section: Introductionmentioning

confidence: 99%

Substrate-induced clustering activates Trim-Away of pathogens and proteins

Zeng

Santos

Mukadam

et al. 2020

Preprint

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SUMMARYTrim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.

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TRIM21—From Intracellular Immunity to Therapy

Cited by 106 publications

References 127 publications

Innate immunity to adenovirus: lessons from mice

Innate immunity to adenovirus: lessons from mice

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

Substrate-induced clustering activates Trim-Away of pathogens and proteins

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