The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis

Zhao, Wenting; Zhou, Chixing; Li, Xuebing; Zhang, Yunfang; Фан, Ли; Fang, Jing

doi:10.1074/jbc.m113.455121

Cited by 16 publications

(12 citation statements)

References 48 publications

(25 reference statements)

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“…Unexpectedly, our network analysis of surface B interactors shows only one relevant cluster accounting for ten ribosomal proteins. Recently, pVHL was proposed to inhibit both ribosome biogenesis and protein synthesis by inducing nuclear retention of pre-40S ribosomal subunits (36). The biological meaning of this interaction is however far from understood.…”

Section: Protein Network Impaired By the Most Frequent Pvhl Mutationsmentioning

confidence: 99%

Genotype-Phenotype Relations of the von Hippel-Lindau Tumor Suppressor Inferred from a Large-Scale Analysis of Disease Mutations and Interactors

Minervini

Quaglia

Tabaro

et al. 2018

Preprint

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Familiar cancers represent a privileged point of view for studying the complex cellular events inducing tumor transformation. Von Hippel-Lindau syndrome, a familiar predisposition to develop cancer is a clear example. Here, we present our efforts to decipher the role of von Hippel-Lindau tumor suppressor protein (pVHL) in cancer insurgence. We collected high quality information about both pVHL mutations and interactors to investigate the association between patient phenotypes, mutated protein surface and impaired interactions. Our data suggest that different phenotypes correlate with localized perturbations of the pVHL structure, with specific cell functions associated to different protein surfaces. We propose five different pVHL interfaces to be selectively involved in modulating proteins regulating gene expression, protein homeostasis as well as to address extracellular matrix (ECM) and ciliogenesis associated functions. These data were used to drive molecular docking of pVHL with its interactors and guide Petri net simulations of the most promising alterations. We predict that disruption of pVHL association with certain interactors can trigger tumor transformation, inducing metabolism imbalance and ECM remodeling. Collectively taken, our findings provide novel insights into VHL-associated tumorigenesis. This highly integrated in silico approach may help elucidate novel treatment paradigms for VHL disease. Author summaryCancer is generally caused by a series of mutations accumulating over time in a healthy tissue, which becomes re-programmed to proliferate at the expense of the hosting organism. This process is difficult to follow and understand as events in a multitude of different genes can lead to similar outcomes without apparent cause. The von Hippel-Lindau (VHL) tumor suppressor is one of the few genes harboring a familiar cancer syndrome, i.e. VHL mutations are known to cause a predictable series of events leading cancer in the kidneys and a few selected other tissues. This article describes a large-scale analysis to relate known VHL mutations to specific cancer pathways by looking at the molecular interactions.Different cancer types appear to be caused by mutations changing the surface of specific parts of the VHL protein. By looking at the VHL interactors involved, it is therefore possible to identify other candidate genes for mutations leading to very similar cancer types.

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Section: Protein Network Impaired By the Most Frequent Pvhl Mutationsmentioning

confidence: 99%

Genotype-Phenotype Relations of the von Hippel-Lindau Tumor Suppressor Inferred from a Large-Scale Analysis of Disease Mutations and Interactors

Minervini

Quaglia

Tabaro

et al. 2018

Preprint

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“…The target sequences for B-Myb#1 and B-Myb#2 were 5=-GACAATGCTGTGAAGAATCAC-3= and 5=-GTCTGTCCTTCC TGGATTCCT-3=, respectively, and those for Skp2#1 and Skp2#2 were 5=-AAGGGAGTGACAAAGACTTTG-3= and 5=-GCATGTACAGGTGG CTGTT-3=, respectively. Knockdown of pVHL or HIF-1␣ was performed as described previously (29,30).…”

Section: Methodsmentioning

confidence: 99%

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Okumura

Uematsu

Byrne

et al. 2016

Molecular and Cellular Biology

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U biquitin-mediated proteolysis by the 26S proteasome plays an important role in the elimination of short-lived proteins (1), including those involved in cell cycle progression, cellular signaling in response to environmental stress or extracellular ligands, morphogenesis, secretion, DNA repair, and organelle biogenesis (2, 3). The pathway consists of two key steps, namely, the covalent attachment of multiple ubiquitin molecules to a target protein and the degradation of the ubiquitinated protein by the 26S proteasome complex. Several components act in concert to attach ubiquitin to a target protein, including a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein isopeptide ligase (E3). E3 is directly responsible for substrate recognition. On the basis of structural similarity, E3 enzymes are classified into three families: the HECT (homologous to E6-AP COOH terminus) family, the U-box family, and the RING finger-containing protein family.The elongin B and C-Cul2 or Cul5-SOCS box protein (ECS) family belongs to the cullin RING ligase (CRL) superfamily (4). pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a member of the ECS family. pVHL forms a complex with elongins B and C, Cul2, and the RING finger protein Rbx1 (5, 6). The CRL2 pVHL complex has ubiquitin ligase activity and targets the hypoxia-inducible factor ␣ (HIF-␣) family of transcription factors (HIF-1 to -3␣) for proteasomal degradation (7). At normal oxygen levels, proline residues in the LXXLAP sequence motif of HIF-␣ proteins are hydroxylated by three prolyl hydroxylases (PHD1 to -3), and an in-depth study revealed that PHD2 is a critical enzyme for the hydroxylation of HIF-1␣ (8, 9). Hydroxylated HIF-␣ is targeted by pVHL for polyubiquitination and proteasomal degradation (10-12). Under conditions of hypoxia (low oxygen level), HIF-␣ is not hydroxylated by PHDs and is therefore not recognized or targeted for degradation by pVHL. The unhydroxylated HIF-␣ dimerizes with constitutively expressed HIF-1␤, also known as an aryl hydrocarbon receptor nuclear translocator (ARNT), and translocates to the nucleus, where it induces the transcription of downstream target genes, including the genes coding for vascular endothelial growth factor A (VEGFA), solute carrier family 2 member 1 (SLC2A1; also known as GLUT1), and platelet-derived growth factor (PDGF) (13). Loss of functional pVHL protein prevents the O 2 -dependent degradation of HIF-␣, resulting in constitutive expression of HIF-dependent genes and VHL disease, which is characterized by a variety of lesions, including hemangioblastomas, renal clear cell carcinomas, pheochromocytomas, pancreatic islet cell tumors, endolymphatic sac tumors, and papillary cystadenomas of the broad ligament (females) and epididymis (males) (13).Studies showing that heterozygous pVHL ϩ/Ϫ mice are phenotypically normal and VHL Ϫ/Ϫ mice die at embryonic day 10.5 (E10.5) to E12.5 (14), together with the existence of many pVHLinteracting proteins (13), a...

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“…Therefore, considering the primary role of HIF 1α in immune defense, it is not surprising that cells have evolved auxillary mechanisms to rapidly sustain the stabilization of HIF 1α, for instance through the degradation of VHL protein. Recently, VHL has also been implicated in regulating protein synthesis by binding ribosomal proteins and preventing ribosome assembly (55). Because viral infection requires a functional protein synthesis apparatus, it makes VHL an attractive viral target.…”

Section: E G F P P E G F P -S O C S 1 B O X P E G F P -S O C S 3 B O mentioning

confidence: 99%

BC-box protein domain-related mechanism for VHL protein degradation

Pozzebon

Varadaraj

Mattoscio

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasomedependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.ubiquitylation | oncoviral proteins | hypoxia U biquitylation is a posttranslational modification that involves the tagging of protein substrates with ubiquitin moieties. Ubiquitin transfer requires the coordinated and subsequent activities of the ubiquitin-activating E1 enzyme, ubiquitin-conjugating E2 enzymes, and ubiquitin E3 ligases. E3 ligases show substrate specificity and can be grouped into three families based on their different E2-docking domains. CRLs (Cullin RING Ligases) are the largest subfamily of RING domain ligases (1). They display the same modular structure: a scaffold subunit (Cullin), a RING subunit, an adaptor, and a substrate-receptor subunit to recruit the specific protein target to be ubiquitylated (2). Each Cullin associates with a specific adaptor subunit, except for Cullin2 and Cullin5, which both interact with the Elongin B and Elongin C (hereafter EloB/C) heterodimer (3). The EloB/C heterodimer is specifically bound by substrate receptors that contain a minimal consensus sequence (called BC-box motif) (4-6) usually included in the SOCS (Suppressor of Cytokine Signaling) domain of several substrate-receptor subunits (7,8). The consensus sequence and the function of the BC-box motif were first described for SOCS proteins (5, 8, 9), a family of downstream effectors of cytokine signaling cascade, involved in the negative feedback regulation of this pathway.Several viruses encode for their own substrate receptors possessing the BC-box motif and are thus able to interact with EloB/ C cellular adaptor, thereby modifying the cellular ubiquitin E3 ligase complex and their target proteins selection (10-17). We have demonstrated that the CELO (Chicken Embryo Lethal Orphan) Adenovirus early protein Gam1 is one of such BC boxcontaining proteins that is able to associate with both Cullin2 and Cullin5 to reconstitute active E3 ligase complexes and tar...

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The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis

Cited by 16 publications

References 48 publications

Genotype-Phenotype Relations of the von Hippel-Lindau Tumor Suppressor Inferred from a Large-Scale Analysis of Disease Mutations and Interactors

Genotype-Phenotype Relations of the von Hippel-Lindau Tumor Suppressor Inferred from a Large-Scale Analysis of Disease Mutations and Interactors

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

BC-box protein domain-related mechanism for VHL protein degradation

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