p97/UBXD1 Generate Ubiquitylated Proteins That Are Sequestered into Nuclear Envelope Herniations in Torsin-Deficient Cells

Prophet, Sarah; Naughton, Brigitte S.; Schlieker, Christian

doi:10.3390/ijms23094627

Cited by 7 publications

(4 citation statements)

References 69 publications

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“…The fact that UBXD1 contains a ubiquitin binding site within the eUBX domain raises the question what role this binding may play in the context of p97-mediated unfolding of ubiquitylated substrate proteins. UBXD1 has been linked to various cellular processes that mostly involve processing of substrates with K48-linked ubiquitin chains 19,31,32 .…”

Section: Ubxd1 Binds Short Ubiquitin Chainsmentioning

confidence: 99%

The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase

Blueggel,

Kroening,

Kracht

et al. 2023

Nat Commun

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The AAA+ ATPase p97/VCP together with different sets of substrate-delivery adapters and accessory cofactor proteins unfolds ubiquitinated substrates to facilitate degradation by the proteasome. The UBXD1 cofactor is connected to p97-associated multisystem proteinopathy but its biochemical function and structural organization on p97 has remained largely elusive. Using a combination of crosslinking mass spectrometry and biochemical assays, we identify an extended UBX (eUBX) module in UBXD1 related to a lariat in another cofactor, ASPL. Of note, the UBXD1-eUBX intramolecularly associates with the PUB domain in UBXD1 close to the substrate exit pore of p97. The UBXD1 PUB domain can also bind the proteasomal shuttling factor HR23b via its UBL domain. We further show that the eUBX domain has ubiquitin binding activity and that UBXD1 associates with an active p97-adapter complex during substrate unfolding. Our findings suggest that the UBXD1-eUBX module receives unfolded ubiquitinated substrates after they exit the p97 channel and before hand-over to the proteasome. The interplay of full-length UBXD1 and HR23b and their function in the context of an active p97:UBXD1 unfolding complex remains to be studied in future work.

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Section: Ubxd1 Binds Short Ubiquitin Chainsmentioning

confidence: 99%

The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase

Blueggel,

Kroening,

Kracht

et al. 2023

Nat Commun

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“…In addition to the various protein interactions required by p97 to perform its designated protein extraction, p97 also requires the deubiquitinylase activity provided by various deubiquitinating enzymes (DUBs). [254][255][256] DUBs play a role in regulating the ubiquitin chain length, which is considered crucial for optimal proteasomal binding.…”

Section: Deubiquitinating Enzymesmentioning

confidence: 99%

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

Badawi

Mohamed

Varghese

et al. 2023

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Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.

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“…Subsequently, additional Nups appear to be recruited, perhaps exerting mechanical force to deform the NE. The local fusion between the INM and ONM seems to require Torsins (Laudermilch et al, 2016 ; Rampello et al, 2020 ; Prophet et al, 2022 ), but is otherwise only poorly understood.…”

Section: Introductionmentioning

confidence: 99%

A checkpoint function for Nup98 in nuclear pore formation suggested by novel inhibitory nanobodies

Solà Colom,

Fu,

Gunkel

et al. 2024

EMBO J

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Nuclear pore complex (NPC) biogenesis is a still enigmatic example of protein self-assembly. We now introduce several cross-reacting anti-Nup nanobodies for imaging intact nuclear pore complexes from frog to human. We also report a simplified assay that directly tracks postmitotic NPC assembly with added fluorophore-labeled anti-Nup nanobodies. During interphase, NPCs are inserted into a pre-existing nuclear envelope. Monitoring this process is challenging because newly assembled NPCs are indistinguishable from pre-existing ones. We overcame this problem by inserting Xenopus-derived NPCs into human nuclear envelopes and using frog-specific anti-Nup nanobodies for detection. We further asked whether anti-Nup nanobodies could serve as NPC assembly inhibitors. Using a selection strategy against conserved epitopes, we obtained anti-Nup93, Nup98, and Nup155 nanobodies that block Nup–Nup interfaces and arrest NPC assembly. We solved structures of nanobody-target complexes and identified roles for the Nup93 α-solenoid domain in recruiting Nup358 and the Nup214·88·62 complex, as well as for Nup155 and the Nup98 autoproteolytic domain in NPC scaffold assembly. The latter suggests a checkpoint linking pore formation to the assembly of the Nup98-dominated permeability barrier.

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p97/UBXD1 Generate Ubiquitylated Proteins That Are Sequestered into Nuclear Envelope Herniations in Torsin-Deficient Cells

Cited by 7 publications

References 69 publications

The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase

The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

A checkpoint function for Nup98 in nuclear pore formation suggested by novel inhibitory nanobodies

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