The E3 Ubiquitin Ligase MARCH8 Regulates TNF‐α‐Induced Apoptosis in Hippocampal Neurons by Targeting Myosin Light Chain 2 for Degradation

Guo, Shanglin; Zhang, Yongqing; Wei, Chaoping; Shi, Lu; Feng, Yali

doi:10.1002/ar.24238

Cited by 6 publications

(6 citation statements)

References 43 publications

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“…As an E3 ubiquitin ligase, MARCH8 could use the ubiquitin–proteasome system (UPS) to degrade targeted proteins [ 47 ]. To evaluate whether MARCH8 could promote ABCB1 ubiquitination, we transfected MARCH8, ubiquitin (Ub), and ABCB1 plasmids into HEK293T cells, and 48 h later, polyubiquitinated ABCB1 proteins were detected using an anti-hemagglutinin (anti-HA) antibody ( Figure 7 D).…”

Section: Resultsmentioning

confidence: 99%

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Zou

Zeng

et al. 2021

Biomedicines

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The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

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Section: Resultsmentioning

confidence: 99%

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Zou

Zeng

et al. 2021

Biomedicines

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“…Our study reports a novel function of MARCH8 in ubiquitinating and degrading a nonmembrane protein, STAT3, through the proteasomal degradation pathway, in addition to a more typical membrane protein target, CD44, through the lysosomal degradation pathway. MARCH8 is expressed widely in early and late endosomes of human tissues and cells, and it plays an important role in immune responses [ 29 , 31 , 32 , 33 , 34 ]. In this study, we elucidated the function of MARCH8 in cell survival, tumorigenesis, and metastasis in breast cancer, in which CD44 [ 15 , 20 , 21 , 35 ] and STAT3 [ 22 , 23 ] are known to contribute to the phenotypic functions mediated by cancer stem cells.…”

Section: Discussionmentioning

confidence: 99%

MARCH8 Suppresses Tumor Metastasis and Mediates Degradation of STAT3 and CD44 in Breast Cancer Cells

Chen

Patel

Jia

et al. 2021

Cancers

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Protein stability is largely regulated by post-translational modifications, such as ubiquitination, which is mediated by ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin ligase E3 with substrate specificity. Membrane-associated RING-CH (MARCH) proteins represent one novel family of transmembrane E3 ligases which target glycoproteins for lysosomal destruction. While most of the MARCH family members are known to degrade membrane proteins in immune cells, their tumor-intrinsic role is largely unknown. In this study, we found that the expression of one MARCH family member, MARCH8, is specifically downregulated in breast cancer tissues and positively correlated with breast cancer survival rate according to bioinformatic analysis of The Cancer Genomic Atlas (TCGA) dataset. MARCH8 protein expression was also lower in a variety of human breast cancer cell lines in comparison to immortalized human mammary epithelial MCF-12A cells. Restoration of MARCH8 expression induced apoptosis in human breast cancer cell lines MDA-MB-231 and BT549. Stable expression of MARCH8 inhibited tumorigenesis and lung metastases of MDA-MB-231 cells in mice. Moreover, we discovered that the breast cancer stem-cell marker and metastasis driver CD44, a membrane protein, interacts with MARCH8 and is one of the glycoprotein targets subject to MARCH8-dependent lysosomal degradation. Unexpectedly, we identified a nonmembrane protein, signal transducer and transcription activator 3 (STAT3), as another essential ubiquitination target of MARCH8, whose degradation through the proteasome pathway is responsible for the proapoptotic changes mediated by MARCH8. These findings highlight a novel tumor-suppressing function of MARCH8 in targeting both membrane and nonmembrane protein targets required for the survival and metastasis of breast cancer cells.

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“…Phosphorylation of myosin-light-chain kinase could induce the involvement of related antibodies to decrease blood-brain barrier permeability (Liu et al, 2018). The degradation of myosin light chain 2 activated cellular apoptosis in Alzheimer's and Parkinson's disease (Guo et al, 2019;Wang et al, 2019). Myosin light chain kinase (MLCK) activates the JNK (c-Jun N-terminal kinase) signaling pathway to facilitate neuronal apoptosis in high glucose-induced hippocampal neurons (Xu et al, 2021) (Figure 3).…”

Section: Regulatory Myosin Light Chains Related Mechanismmentioning

confidence: 99%

Background and roles: myosin in autoimmune diseases

Fu,

Zou,

et al. 2023

Front. Cell Dev. Biol.

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The myosin superfamily is a group of molecular motors. Autoimmune diseases are characterized by dysregulation or deficiency of the immune tolerance mechanism, resulting in an immune response to the human body itself. The link between myosin and autoimmune diseases is much more complex than scientists had hoped. Myosin itself immunization can induce experimental autoimmune diseases of animals, and myosins were abnormally expressed in a number of autoimmune diseases. Additionally, myosin takes part in the pathological process of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, autoimmune myocarditis, myositis, hemopathy, inclusion body diseases, etc. However, research on myosin and its involvement in the occurrence and development of diseases is still in its infancy, and the underlying pathological mechanisms are not well understood. We can reasonably predict that myosin might play a role in new treatments of autoimmune diseases.

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The E3 Ubiquitin Ligase MARCH8 Regulates TNF‐α‐Induced Apoptosis in Hippocampal Neurons by Targeting Myosin Light Chain 2 for Degradation

Cited by 6 publications

References 43 publications

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

MARCH8 Suppresses Tumor Metastasis and Mediates Degradation of STAT3 and CD44 in Breast Cancer Cells

Background and roles: myosin in autoimmune diseases

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