SFI1 promotes centriole duplication by recruiting USP9X to stabilize the microcephaly protein STIL

Kodani, Andrew; Moyer, Tyler C.; Chen, Allen; Holland, Andrew J.; Walsh, Christopher A.; Reiter, Jeremy F.

doi:10.1083/jcb.201803041

Cited by 20 publications

(38 citation statements)

References 75 publications

(114 reference statements)

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“…Generally, human DUB can accurately identify the ubiquitinated protein substrate and effectively cleave the ubiquitin chain on the substrate to enhance its stability and ensure the balance of the ubiquitination process [ 9 ]. Abnormal DUB is implicated in multiple diseases, such as cancer, cardiovascular disease, and neurologic disorder [ 10 – 12 ]. DUB is overexpressed in several cancers and promotes tumor development by stabilizing certain oncoproteins, such as androgen receptor, c-Myc, and Snail [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

Liao

Shao

Liu

et al. 2021

J Exp Clin Cancer Res

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Background Hepatocellular carcinoma (HCC) remains a medical challenge due to its high proliferation and metastasis. Although deubiquitinating enzymes (DUBs) play a key role in regulating protein degradation, their pathological roles in HCC have not been fully elucidated. Methods By using biomass spectrometry, co-immunoprecipitation, western blotting and immunofluorescence assays, we identify ribosomal protein S16 (RPS16) as a key substrate of ubiquitin-specific peptidase 1 (USP1). The role of USP1-RPS16 axis in the progression of HCC was evaluated in cell cultures, in xenograft mouse models, and in clinical observations. Results We show that USP1 interacts with RPS16. The depletion of USP1 increases the level of K48-linked ubiquitinated-RPS16, leading to proteasome-dependent RPS16 degradation. In contrast, overexpression of USP1-WT instead of USP1-C90A (DUB inactivation mutant) reduces the level of K48-linked ubiquitinated RPS16, thereby stabilizing RPS16. Consequently, USP1 depletion mimics RPS16 deficiency with respect to the inhibition of growth and metastasis, whereas transfection-enforced re-expression of RPS16 restores oncogenic-like activity in USP1-deficient HCC cells. Importantly, the high expression of USP1 and RPS16 in liver tissue is a prognostic factor for poor survival of HCC patients. Conclusions These findings reveal a previously unrecognized role for the activation of USP1-RPS16 pathway in driving HCC, which may be further developed as a novel strategy for cancer treatment.

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Section: Introductionmentioning

confidence: 99%

USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

Liao

Shao

Liu

et al. 2021

J Exp Clin Cancer Res

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“…An interaction between centrin and centrosomal Sfi1p is required for duplication of the yeast spindle pole body, and in mammalian cells, the mammalian ortholog SFI1 promotes centriole duplication (Kilmartin, 2003;Kodani et al, 2019). Structural studies of Sfi1 uncovered centrin-binding repeats (CBRs) that each contain a conserved sequence motif, Ax 7 LLx 3 F/Lx 2 WK/R, that directly binds the C-terminus of centrin (Kilmartin, 2003;Li et al, 2006;Martinez-Sanz et al, 2010.…”

Section: Introductionmentioning

confidence: 99%

Tetrahymena Poc5 is a transient basal body component that is important for basal body maturation

Heydeck

Bayless

Stemm-Wolf

et al. 2020

Journal of Cell Science

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Basal bodies (BBs) are microtubule-based organelles that act as a template for and stabilize cilia at the cell surface. Centrins ubiquitously associate with BBs and function in BB assembly, maturation and stability. Human POC5 (hPOC5) is a highly conserved centrin-binding protein that binds centrins through Sfi1p-like repeats and is required for building full-length, mature centrioles. Here, we use the BB-rich cytoskeleton of Tetrahymena thermophila to characterize Poc5 BB functions. Tetrahymena Poc5 (TtPoc5) uniquely incorporates into assembling BBs and is then removed from mature BBs prior to ciliogenesis. Complete genomic knockout of TtPOC5 leads to a significantly increased production of BBs, yet a markedly reduced ciliary density, both of which are rescued by reintroduction of TtPoc5. A second Tetrahymena POC5-like gene, SFR1, is similarly implicated in modulating BB production. When TtPOC5 and SFR1 are co-deleted, cell viability is compromised and BB overproduction is exacerbated. Overproduced BBs display defective transition zone formation and a diminished capacity for ciliogenesis. This study uncovers a requirement for Poc5 in building mature BBs, providing a possible functional link between hPOC5 mutations and impaired cilia. This article has an associated First Person interview with the first author of the paper.

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“…First, as described above, USP9X regulates TGF-β signaling through deubiquitylating SMAD4 and this pathway is defective in patient fibroblasts [ 199 ]. Second, USP9X has been shown to control centriole duplication and centrosome biogenesis through e.g., deubiquitylating and stabilizing the centriole duplication factor STIL [ 201 – 203 ] as well as cilia assembly through regulating the localization and stability of the ciliogenesis-promoting factor NPHP5 [ 204 ]. Mutations in genes regulating these processes (including STIL and ICQB1 encoding for NPHP5) frequently result in primary microcephaly [ 205 , 206 ] and ciliopathies [ 207 , 208 ], respectively, with considerable phenotypic overlap with USP9X patients, thus suggesting that aberrant centrosome duplication and cilia assembly could contribute to MRX99.…”

Section: Dysregulation Of Dubs Results In Developmental Diseasesmentioning

confidence: 99%

“…For instance, many DUBs of the USP family encode substrate interaction motifs and cleave ubiquitin chains from substrates (base cleavage) [22], while other DUBs prefer to cleave ubiquitin chains from the middle (endo-cleavage, e.g., most OTU DUBs [61]) or from the distal or proximal end of the chain (distal exo cleavage, e.g., MINDY [51,62], and proximal exo-cleavage, e.g., USP5 [63], respectively). In addition, some DUBs display exquisite linkage specificity (e.g., some members of the OTUs [61], JAMMs [64][65][66], [195,199] Loss-of-function; hemizygous mutations [195,199] Decreased TGF-β signaling (SMAD4/SMURF1) [199]; impaired centriole duplication (STIL) and cilia formation (NPHP5) [201,204]; impaired dendritic spine formation and maintenance (ankyrin-G) [144,145] USP9X Mental retardation, X-linked 99, syndromic (MIM: 300968) Female-restricted, intellectual disability associated with characteristic facial features, short stature, cardiac, and structural brain abnormalities [197,198] Loss-of-function; heterozygous missense and nonsense mutations [197,198] Decreased TGF-β signaling (SMAD4/SMURF1) [199]; impaired centriole duplication (STIL) and cilia formation (NPHP5) [201,204]; impaired dendritic spine formation and maintenance (ankyrin-G) [144,145] OTUD5 LINKED syndrome Global developmental delay, intellectual disability, central nervous system, craniofacial, cardiac, skeletal, and genitourinary anomalies [41] Loss-of-function; hemizygous deletion and missense mutations that affect protein levels, localization, and catalytic activity [41] Impaired chromatin remodeling at neuroectodermal enhancers due to aberrant degradation of chromatin regulators (e.g., ARID1A/B, HDAC2, HCF1) [41] OTUD6B Multiple congenital anomaly disorder (MIM:617452) Global developmental delay, feeding diffi...…”

Section: Dubs Can Remove Ubiquitin From Substrates or Cleave Ubiquitimentioning

confidence: 99%

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020

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Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.

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SFI1 promotes centriole duplication by recruiting USP9X to stabilize the microcephaly protein STIL

Abstract: Kodani et al. identify a role for the mammalian homologue of yeast SFI1 as a regulator of centriole duplication. They show that SFI1 localizes USP9X to the centrosome to stabilize the microcephaly protein STIL to promote centriole duplication.

Cited by 20 publications

References 75 publications

USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

Tetrahymena Poc5 is a transient basal body component that is important for basal body maturation

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

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