Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan

ABSTRACT: Xenophagy, also known as antibacterial selective autophagy, degrades invading bacterial pathogens such as group A Streptococcus (GAS) to defend cells. Although invading bacteria are known to be marked with ubiquitin and selectively targeted by xenophagy, how ubiquitin ligases recognize invading bacteria is poorly understood. Here, we show that FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS. FBXO2 targets cytosolic GAS through its sugar-binding motif and GlcNAc expression on the GAS surface. FBXO2 knockout resulted in decreased ubiquitin accumulation on intracellular GAS and xenophagic degradation of bacteria. Furthermore, SCF components such as SKP1, CUL1, and ROC1 are required for ubiquitin-mediated xenophagy against GAS. Thus, SCFFBXO2 recognizes GlcNAc residues of GAS surface carbohydrates and functions in ubiquitination during xenophagy.

SUBMITTER: Mr. Akihiro Yamada

PROVIDER: S-SCDT-EMBOR-2021-52584-T | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan.

Project description:Xenophagy, also known as antibacterial selective autophagy, degrades invading bacterial pathogens such as group A Streptococcus (GAS) to defend cells. Although invading bacteria are known to be marked with ubiquitin and selectively targeted by xenophagy, how ubiquitin ligases recognize invading bacteria is poorly understood. Here, we show that FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS. FBXO2 targets cytosolic GAS through its sugar-binding motif and GlcNAc expression on the GAS surface. FBXO2 knockout resulted in decreased ubiquitin accumulation on intracellular GAS and xenophagic degradation of bacteria. Furthermore, SCF components such as SKP1, CUL1, and ROC1 are required for ubiquitin-mediated xenophagy against GAS. Thus, SCFFBXO2 recognizes GlcNAc residues of GAS surface carbohydrates and functions in ubiquitination during xenophagy.

| S-EPMC8567282 | biostudies-literature

An Atypical SCF-like Ubiquitin Ligase Complex Promotes Wallerian Degeneration through Regulation of Axonal Nmnat2.

Project description:Axon degeneration is a tightly regulated, self-destructive program that is a critical feature of many neurodegenerative diseases, but the molecular mechanisms regulating this program remain poorly understood. Here, we identify S-phase kinase-associated protein 1A (Skp1a), a core component of a Skp/Cullin/F-box (SCF)-type E3 ubiquitin ligase complex, as a critical regulator of axon degeneration after injury in mammalian neurons. Depletion of Skp1a prolongs survival of injured axons in vitro and in the optic nerve in vivo. We demonstrate that Skp1a regulates the protein level of the nicotinamide adenine dinucleotide (NAD)+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) in axons. Loss of axonal Nmnat2 contributes to a local ATP deficit that triggers axon degeneration. Knockdown of Skp1a elevates basal levels of axonal Nmnat2, thereby delaying axon degeneration through prolonged maintenance of axonal ATP. Consistent with Skp1a functioning through regulation of Nmnat2, Skp1a knockdown fails to protect axons from Nmnat2 knockdown. These results illuminate the molecular mechanism underlying Skp1a-dependent axonal destruction.

| S-EPMC5075525 | biostudies-literature

Ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase Skp1-cullin-F-box ligase (SCF) interact through multiple conformations.

Project description:In the ubiquitin-proteasome system, protein substrates are degraded via covalent modification by a polyubiquitin chain. The polyubiquitin chain must be assembled rapidly in cells, because a chain of at least four ubiquitins is required to signal for degradation, and chain-editing enzymes in the cell may cleave premature polyubiquitin chains before achieving this critical length. The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association. This rapid association has been attributed to electrostatic interactions between the acidic C-terminal tail of Cdc34 and a feature on SCF called the basic canyon. However, the structural aspects of the Cdc34-SCF interaction and how they permit rapid complex formation remain elusive. Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. We discuss how these results can explain the rapid association of Cdc34 and SCF.

| S-EPMC4294478 | biostudies-literature

Signal-induced disassembly of the SCF ubiquitin ligase complex by Cdc48/p97.

Project description:A large group of E3 ubiquitin ligases is formed by the multisubunit SCF complex, whose core complex (Rbx1/Cul1-Cdc53/Skp1) binds one of many substrate recruiting F-box proteins to form an array of SCF ligases with diverse substrate specificities. It has long been thought that ubiquitylation by SCF ligases is regulated at the level of substrate binding. Here we describe an alternative mechanism of SCF regulation by active dissociation of the F-box subunit. We show that cadmium stress induces selective recruitment of the AAA(+) ATPase Cdc48/p97 to catalyze dissociation of the F-box subunit from the yeast SCF(Met30) ligase to block substrate ubiquitylation and trigger downstream events. Our results not only provide an additional layer of ubiquitin ligase regulation but also suggest that targeted, signal-dependent dissociation of multisubunit enzyme complexes is an important mechanism in control of enzyme function.

| S-EPMC3483439 | biostudies-literature

Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase.

Project description:The SCF(Fbw7) ubiquitin ligase complex plays important roles in cell growth, survival, and differentiation via the ubiquitin-proteasome-mediated regulation of protein stability. Fbw7 (also known as Fbxw7, Sel-10, hCdc4, or hAgo), a substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, facilitates the degradation of several proto-oncogene products by the proteasome. Given that mutations in Fbw7 are found in various types of human cancers, Fbw7 is considered to be a potent tumor suppressor. In the present study, we show that E1A, an oncogene product derived from adenovirus, interferes with the activity of the SCF(Fbw7) ubiquitin ligase. E1A interacted with SCF(Fbw7) and attenuated the ubiquitylation of its target proteins in vivo. Furthermore, using in vitro purified SCF(Fbw7) component proteins, we found that E1A directly bound to Roc1/Rbx1 and CUL1 and that E1A inhibited the ubiquitin ligase activity of the Roc1/Rbx1-CUL1 complex but not that of another RING-type ubiquitin ligase, Mdm2. Ectopically expressed E1A interacted with cellular endogenous Roc1/Rbx1 and CUL1 and decelerated the degradation of several protooncogene products that were degraded by SCF(Fbw7) ubiquitin ligase. Moreover, after wild-type adenovirus infection, adenovirus-derived E1A interacted with endogenous Roc1/Rbx1 and decelerated degradation of the endogenous target protein of SCF(Fbw7). These observations demonstrated that E1A perturbs protein turnover regulated by SCF(Fbw7) through the inhibition of SCF(Fbw7) ubiquitin ligase. Our findings may help to explain the mechanism whereby adenovirus infection induces unregulated proliferation.

| S-EPMC2788827 | biostudies-literature

PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2.

Project description:PHR (PAM/Highwire/RPM-1) proteins are conserved RING E3 ubiquitin ligases that function in developmental processes, such as axon termination and synapse formation, as well as axon degeneration. At present, our understanding of how PHR proteins form ubiquitin ligase complexes remains incomplete. Although genetic studies indicate NMNAT2 is an important mediator of PHR protein function in axon degeneration, it remains unknown how PHR proteins inhibit NMNAT2. Here, we decipher the biochemical basis for how the human PHR protein PAM, also called MYCBP2, forms a noncanonical Skp/Cullin/F-box (SCF) complex that contains the F-box protein FBXO45 and SKP1 but lacks CUL1. We show FBXO45 does not simply function in substrate recognition but is important for assembly of the PAM/FBXO45/SKP1 complex. Interestingly, we demonstrate a novel role for SKP1 as an auxiliary component of the target recognition module that enhances binding of FBXO45 to NMNAT2. Finally, we provide biochemical evidence that PAM polyubiquitinates NMNAT2 and regulates NMNAT2 protein stability and degradation by the proteasome.

| S-EPMC6130950 | biostudies-literature

Identification of an SCF ubiquitin-ligase complex required for auxin response in Arabidopsis thaliana.

Project description:The plant hormone auxin regulates diverse aspects of plant growth and development. We report that in Arabidopsis, auxin response is dependent on a ubiquitin-ligase (E3) complex called SCFTIR1. The complex consists of proteins related to yeast Skp1p and Cdc53p called ASK and AtCUL1, respectively, as well as the F-box protein TIR1. Mutations in either ASK1 or TIR1 result in decreased auxin response. Further, overexpression of TIR1 promotes auxin response suggesting that SCFTIR1 is limiting for the response. These results provide new support for a model in which auxin action depends on the regulated proteolysis of repressor proteins.

| S-EPMC316846 | biostudies-literature

Gln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8.

Project description:The full enzymatic activity of the cullin-RING ubiquitin ligases (CRLs) requires a ubiquitin-like protein (that is, Nedd8) modification. By deamidating Gln40 of Nedd8 to glutamate (Q40E), the bacterial cycle-inhibiting factor (Cif) family is able to inhibit CRL E3 activities, thereby interfering with cellular functions. Despite extensive structural studies on CRLs, the molecular mechanism by which Nedd8 Gln40 deamidation affects CRL functions remains unclear. We apply a new quantitative cross-linking mass spectrometry approach to characterize three different types of full-length human Cul1-Rbx1 complexes and uncover major Nedd8-induced structural rearrangements of the CRL1 catalytic core. More importantly, we find that those changes are not induced by Nedd8(Q40E) conjugation, indicating that the subtle change of a single Nedd8 amino acid is sufficient to revert the structure of the CRL catalytic core back to its unmodified form. Our results provide new insights into how neddylation regulates the conformation and activity of CRLs.

| S-EPMC4686759 | biostudies-literature

Systemwide disassembly and assembly of SCF ubiquitin ligase complexes.

Project description:Cells respond to environmental cues by remodeling their inventories of multiprotein complexes. Cellular repertoires of SCF (SKP1-CUL1-F box protein) ubiquitin ligase complexes, which mediate much protein degradation, require CAND1 to distribute the limiting CUL1 subunit across the family of ∼70 different F box proteins. Yet, how a single factor coordinately assembles numerous distinct multiprotein complexes remains unknown. We obtained cryo-EM structures of CAND1-bound SCF complexes in multiple states and correlated mutational effects on structures, biochemistry, and cellular assays. The data suggest that CAND1 clasps idling catalytic domains of an inactive SCF, rolls around, and allosterically rocks and destabilizes the SCF. New SCF production proceeds in reverse, through SKP1-F box allosterically destabilizing CAND1. The CAND1-SCF conformational ensemble recycles CUL1 from inactive complexes, fueling mixing and matching of SCF parts for E3 activation in response to substrate availability. Our data reveal biogenesis of a predominant family of E3 ligases, and the molecular basis for systemwide multiprotein complex assembly.

| S-EPMC10156175 | biostudies-literature

Serine Phosphorylation by mTORC1 Promotes IRS-1 Degradation through SCF?-TRCP E3 Ubiquitin Ligase.

Project description:The insulin receptor substrate IRS-1 is a key substrate of insulin and insulin-like growth factor (IGF) receptor tyrosine kinases that mediates their metabolic and growth-promoting actions. Proteasomal degradation of IRS-1 is induced following activation of the downstream kinase mTOR complex 1 (mTORC1) to constitute a negative feedback loop. However, the underlying mechanism remains poorly understood. Here we report that Ser 422 of IRS-1 is phosphorylated by mTORC1 and required for IRS-1 degradation induced by prolonged IGF stimulation. Phosphorylation of Ser 422 then recruits the SCF?-TRCP E3 ligase complex, which catalyzes IRS-1 ubiquitination. Phosphorylation-dependent IRS-1 degradation contributes to impaired growth and survival responses to IGF in cells lacking TSC2, a negative regulator of mTORC1. Inhibition of IRS-1 degradation promotes sustained Akt activation in IGF-stimulated cells. Our work clarifies the nature of the IRS-1-mTORC1 feedback loop and elucidates its role in temporal regulation of IGF signaling.

| S-EPMC6123863 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data