The Ubiquitination-Dependent and -Independent Functions of Cereblon in Cancer and Neurological Diseases

Zhou, Liang; Xu, Guoqiang

doi:10.1016/j.jmb.2022.167457

Cited by 6 publications

(4 citation statements)

References 95 publications

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“…To test if GFP-tau aggregation was dependent on the presence of recombinant tau seeds, we utilized the tau degrader QC-01-175 (33). This heterobifunctional molecule contains a pomalidomide warhead to recruit the CUL4-RBX1-DDB1-CRBN (CRL4 CRBN ) E3 ubiquitin ligase complex (34) and a second warhead to bring the complex proximal to tau species recognized by the clinical tau positron tomography tracer (PET) tracer T807 (flortaucipir) (35). The resulting ternary complex facilitates tau ubiquitination and subsequent proteasomal degradation of the targeted tau species (Figure 4a) (26).…”

Section: Resultsmentioning

confidence: 99%

Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy

Lam,

Kuo,

Reis

et al. 2023

Preprint

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Tauopathies are a class of neurodegenerative diseases characterized by the progressive misfolding and accumulation of pathological tau protein in focal regions of the brain, leading to insidious neurodegeneration. Abnormalities in cholesterol metabolism and homeostasis have also been implicated in various neurodegenerative diseases. However, the connection between cholesterol dysregulation and tau pathology remains largely unknown. To model and measure the impact of cholesterol dysregulation on tau, we utilized a combination ofin vitroandex vivotau aggregation assays using an engineered tau biosensor cell line and human induced pluripotent stem cell (iPSC)-derived neuronal cultures from an individual harboring an autosomal dominant P301L tau mutation and from a healthy control. We demonstrate that excess cholesterol esters lead to an increased rate of tau aggregationin vitroand an increase in seed-dependent insoluble tau aggregates detected in the biosensor line. We observed a strong correlation between cholesterol ester concentration and the presence of high-molecular-weight, oligomeric tau species. Importantly, in tauopathy patient iPSC-derived neurons harboring a P301L tau mutation with endogenous forms of misfolded tau, we show that acute dysregulation of cholesterol homeostasis through acute exposure to human plasma-purified cholesterol esters formed by the linkage of fatty acids to the hydroxyl group of cholesterol leads to the rapid accumulation of phosphorylated tau. Conversely, treatment with the same cholesterol esters pool did not lead to subsequent accumulation of phosphorylated tau in control iPSC-derived neurons. Finally, treatment with a heterobifunctional, small-molecule degrader designed to selectively engage and catalyze the ubiquitination and proteasomal degradation of aberrant tau species prevented cholesterol ester-induced aggregation of tau in the biosensor cell line in a Cereblon E3 ligase-dependent manner. Degrader treatment also restored the resiliency of tauopathy patient-derived neurons towards cholesterol ester-induced tau aggregation phenotypes. Taken together, our study supports a key role of cholesterol dysregulation in tau aggregation. Moreover, it provides further pre-clinical validation of the therapeutic strategy of targeted protein degradation with heterobifunctional tau degraders for blocking tau seeding.

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Section: Resultsmentioning

confidence: 99%

Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy

Lam,

Kuo,

Reis

et al. 2023

Preprint

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“…IMiDs are widely used as skeletal drugs in MM therapy, including thalidomide and its derivatives LEN and POM, in different MM stages. 25 More than 50% of patients with MM were sensitive and responsive to the initial LEN treatment 26 ; however, with extended treatment time, most patients showed acquired resistance to LEN, leading to disease progression. Interestingly, the molecular basis of IMiD therapy was demonstrated following the clinical application of thalidomide in MM treatment.…”

Section: Discussionmentioning

confidence: 99%

Decreased RNA‐binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to lenalidomide

Lin,

Zhang,

Liu

et al. 2024

Br J Haematol

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SummaryMultiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3′‐untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU‐binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn‐humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.

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“…Interestingly, the protein levels of CRBN and its neo-substrate IKZF1/3 were unaffected in TRAF2 knockout myeloma cells, although these TRAF2 knockout cells were resistant to both lenalidomide and pomalidomide ( 66 ), which suggested that the nonubiquitin functions of CRBN were crucial for cellular responses, such as proliferation. This hypothesis was underscored by the observations that CRBN inhibited NF-κB activation by directly binding to TRAF6 ( 67 , 68 ), thereby exhibiting nonubiquitin-mediated functions ( 69 ). Both caspase-8 and CRBN contributed to NF-κB activation, which further indicated an overlap between caspase-8 and CRBN activities.…”

Section: Caspase-8-induced Cleavage Of Crbn In Myeloma Cellsmentioning

confidence: 99%

Caspase-8: Friend or Foe in Bortezomib/Lenalidomide-Based Therapy for Myeloma

Zhou

2022

Front. Oncol.

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Antiproliferation and proapoptosis are two major molecular mechanisms of action of drugs used for the treatment of multiple myeloma. Proteasome inhibitors, such as bortezomib (PS-341), and immunomodulatory drugs (IMiDs), such as lenalidomide, are the two drug types approved for the treatment of myeloma. Bortezomib and lenalidomide activate caspase-8 and promote the apoptosis of myeloma cells. However, caspase-8 inhibition potentiated the antiproliferative effect of lenalidomide and bortezomib in myeloma cells, suggesting that caspase-8 could regulate proliferation and apoptosis in the opposite pathway. In this mini-review, I summarized recent advances in determining the molecular mechanisms of caspase-8 in bortezomib–lenalidomide-based therapy for myeloma and explored the possible functions of caspase-8 in the proliferation and apoptosis of myeloma cells. Furthermore, future directions of caspase-8-based therapy for myeloma have been discussed.

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The Ubiquitination-Dependent and -Independent Functions of Cereblon in Cancer and Neurological Diseases

Cited by 6 publications

References 95 publications

Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy

Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy

Decreased RNA‐binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to lenalidomide

Caspase-8: Friend or Foe in Bortezomib/Lenalidomide-Based Therapy for Myeloma

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