SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Tamiya, Hironari; Kim, Hyungsoo; Klymenko, Oleksiy; Kim, Heejung; Feng, Yongmei; Zhang, Tongwu; Han, Jee Yun; Murao, Ayako; Snipas, Scott J.; Jilaveanu, Lucia B.; Brown, Kevin M.; Kluger, Harriet M.; Zhang, Hao; Iwaï, Kazuhiro; Ronai, Ze’ev

doi:10.1172/jci95410

Cited by 37 publications

(49 citation statements)

References 41 publications

(43 reference statements)

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“…The functional implications and regulatory mechanisms of SHARPIN need to be explored in detail in both on an immunological basis and therapeutic basis. SHARPIN has been highly explored in many disease conditions, especially in cancer stressing out its multiple roles in many LUBAC-independent regulatory mechanisms [28, 29], suggesting that this modification that we have identified, if not targeted for a proteosomal degradation, might be inhibiting only the LUBAC-dependent SHARPIN function, promoting its other cellular functions, which is out of scope for this study.…”

Section: Discussionmentioning

confidence: 99%

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

Krishnan

Menon

et al. 2019

Preprint

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23 INTRODUCTION: Defective immune cell-mediated clearance of amyloid-beta (Aβ) and 24 Aβ-associated inflammatory activation of immune cells are key contributors of Aβ 25 accumulation and neurodegeneration in Alzheimer's disease (AD), however, the underlying 26 mechanisms remain elusive. 27 METHODS: Differentiated THP-1 cells treated with Aβ and AD patient-derived 28 macrophages were used as in-vitro model. The role of SHARPIN was analysed in 29 differentiated THP-1 cells using siRNA-mediated knockdown followed by immunoblotting, 30 ELISA, real-time PCR, immunoprecipitation and flow cytometry. Differentiated SHSY5Y 31cells were used to study inflammation-mediated apoptosis. 32RESULTS: SHARPIN was found to regulate Aβphagocytosis and NLRP3 expression in 33 THP-1 derived macrophages. Further, it was found to promote macrophage polarization to an 34 M1 (pro-inflammatory) phenotype resulting in enhanced inflammation and associated 35 neuronal death, demonstrated using in-vitro culture systems. SHARPIN expression by blood-36 derived macrophages was further found to be higher in the early stages of AD, which 37 correlates with Aβ 40/42 concentration in the plasma and age of the study subjects. 38DISCUSSION: The novel protein, SHARPIN has been shown to play critical roles in 39 regulation of Aβ-phagocytosis and inflammation in AD and the mechanism by which 40 SHARPIN is activated by Aβ in macrophages has been elucidated. 41 42 Keywords: SHARPIN, amyloid-beta, Alzheimer's disease, mild cognitive impairment, 43 macrophage, NLRP3, inflammation, phagocytosis, oxidative stress. 44 3 Abbreviations: AD, Alzheimer's disease; Aβ, amyloid-beta; MCI, Mild Cognitive 45 Impairment; SHARPIN, Shank-associated RH domain-interacting protein; NLRP3, 46 nucleotide-binding domain (NOD)-like receptor protein 3; ASC, Apoptosis-associated Speck-47 like protein containing a caspase-recruitment domain (CARD); LUBAC, linear 48 ubiquitination assembly complex; iNOS, induced Nitric Oxide Synthase; IL-1β, Interleukin-49 1beta; TGF-β, Transforming Growth Factor-1beta; TNF-α, Tumor Necrosis Factor-alpha; 50 PBMC, Peripheral Blood Mononuclear cells; NF-κB, Nuclear Factor kappa-light chain-51 enhancer of activated B cells; ROS, reactive oxygen species; CRP, C-Reactive Protein; PBS, 52 Phosphate-buffered saline; RPMI, Roswell Park Memorial Institute; FBS, fetal bovine 53 serum; THP-1, Tohoku Hospital Pediatrics-1; NH 4 OH, Ammonium hydroxide; FITC, 54 Fluorescein isothiocyanate. 55 56 57 58 59 60 61 62 63 64 4 polarization to M1 (pro-inflammatory) phenotype in differentiated THP-1 cell line as an in-89 vitro model and SHARPIN silencing protects neurons from Aβ-induced inflammatory 90 damage using differentiated SHSY5Y cell line. Further, utilizing control, mild cognitively 91 impaired (MCI) and AD patient-derived macrophages, we show that SHARPIN plays a 92 significant role the progression of AD. 93 2. Materials and methods 94 2.1. Inclusion of study subjects 95 AD and MCI patients were recruited from the Memory & Neurobehavioral Clinic (MNC) at 96 the S...

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Section: Discussionmentioning

confidence: 99%

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

Krishnan

Menon

et al. 2019

Preprint

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“…The central role for integrin α11, uncovered here, in regulating mechanotransduction on collagen may also be essential to the pathological behavior of fibroblasts in cancerous or fibrotic tissues. As both SHARPIN and integrin α11β1 are significant regulators of cancer tumorigenesis and dissemination, as well as fibroblast contractility and collagen remodeling (He et al, 2010, Navab et al, 2016, Peuhu, Kaukonen et al, 2017, Tamiya et al, 2018, Zhu et al, 2007, increased understanding of their functional interplay is of wide interest. Finally, our finding that the mechanical output of fibroblasts can be strongly influenced by a single parameter of the molecular clutch, the integrin binding dynamics, highlights the tuneability of mechanotransduction, and its ability to trigger specific outputs in response to both internal and external parameters.…”

Section: Discussionmentioning

confidence: 99%

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Lerche

Elosegui‐Artola

Guzmán

et al. 2019

Preprint

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The link between the modulation of integrin activity and cellular mechanosensing of tissue rigidity, especially on different extracellular matrix ligands, remains poorly understood. Here, we find that primary mouse mammary gland stromal fibroblasts (MSFs) are mechanically distinct from previously studied cell types. In particular, MSFs generate high forces at a low matrix stiffness, equivalent to the soft mammary gland tissue, supported by maximal focal adhesion maturation, strong actin stress fiber formation, and myosin phosphorylation.We describe that loss of the cytosolic integrin inhibitor, SHARPIN, triggers impeded spreading of MSFs specifically on soft type I collagen but not on fibronectin. Through quantitative experiments and computational modelling, we find that reduced expression of the collagen-binding integrin α11β1 in SHARPIN-deficient MSFs leads to faster force-induced unbinding of adhesions from collagen. Faster unbinding, in turn, impairs force transmission in these cells, particularly, at the stiffness optimum observed for wild-type cells, and increases actin retrograde flow. Our results unveil a collagen-specific mechanosensing mechanism and suggest a key function for integrin activity regulation and integrin α11β1 in MSF mechanotransduction.

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“…Our studies have identified SKI, a component of a transcriptional repressor complex antagonizing TGFβ signaling, as a substrate for PRMT5-MEP50-SHARPIN, which limits SKI recruitment to SOX10 and PAX3 promoters and derepresses them. In this context, PRMT5 control of SKI enhances melanoma growth by upregulating SOX10 and PAX3, which drive melanoma growth [53].…”

Section: Prmt5 Control Of Gene Expression By Non-histone Proteinsmentioning

confidence: 99%

“…LINC01138, a lncRNA encoded in a genomic region frequently amplified in HCC, binds to and stabilizes PRMT5 protein by interfering with CHIP binding and ubiquitination [114]. Binding of PRMT5 to SHARPIN, a component of the LUBAC complex, implies a possible crosstalk between PRMT5-mediated methylation and LUBAC-driven linear ubiquitination [40,53].…”

Section: Regulation By the Ups (Ubiquitin-proteasome System)mentioning

confidence: 99%

PRMT5 function and targeting in cancer

Kim¹,

Ronai²

2020

CST

Self Cite

139

131

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Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapyresponse. Here we discuss the function of PRMT5, a member of the nine-member PRMT family, in controlling oncogenic processes including tumor intrinsic, as well as extrinsic microenvironmental signaling pathways. We discuss PRMT5 effect on histone methylation and methylation of regulatory proteins including those involved in RNA splicing, cell cycle, cell death and metabolic signaling. In all, we highlight the importance of PRMT5 regulation and function in cancer, which provide the foundation for therapeutic modalities targeting PRMT5.

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SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Cited by 37 publications

References 41 publications

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

PRMT5 function and targeting in cancer

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