PXD042592-1

PXD042592 is an original dataset announced via ProteomeXchange.

Title	The CRL3gigaxonin ubiquitin ligase-USP15 pathway governs the destruction of neurofilament proteins
Description	Giant axonal neuropathy (GAN) is caused by mutations in the GAN gene encoding for gigaxonin (GIG), which functions as an adaptor of the CUL3-RBX1-GIG (CRL3GIG) E3 ubiquitin ligase complex. The pathological hallmark of GAN is characterized by the accumulation of densely packed neurofilaments (NFs) in the axons. However, there are fundamental knowledge gaps in our understanding of the molecular mechanisms by which the ubiquitin-proteasome system controls the homeostasis of NF proteins. Recently, the deubiquitylating enzyme USP15 was reported to play a crucial role in regulating ubiquitylation and proteasomal degradation of CRL4CRBN substrate proteins. Here, we report that the CRL3GIG–USP15 pathway governs the destruction of NF proteins NEFL and INA. We identified a specific degron called NEFLL12 degron for CRL3GIG. Notably, mutations in the C-terminal Kelch domain of GIG, represented by L309R, R545C, and C570Y, disrupted the binding of GIG to NEFL and INA, leading to the accumulation of these NF proteins. This accounts for the loss-of-function mutations in GAN patients. In addition to regulating NFs, CRL3GIG also controls actin filaments by directly targeting actin-filament-binding regulatory proteins TPM1, TPM2, TAGLN, and CNN2 for proteasomal degradation. Thus, our findings broadly impact the field by providing fundamental mechanistic insights into regulating extremely long-lived NF proteins NEFL and INA by the CRL3GIG–USP15 pathway and offering previously unexplored therapeutic opportunities to treat GAN patients and other neurodegenerative diseases by explicitly targeting downstream substrates of CRL3GIG
HostingRepository	PRIDE
AnnounceDate	2025-11-06
AnnouncementXML	Submission_2025-11-06_14:25:14.101.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thao Thi Nguyen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-31 14:44:21	ID requested
⏵ 1	2025-11-06 14:25:15	announced

Park HM, Le L, Nguyen TT, Nam KH, Ordureau A, Lee JE, Nguyen TV, ubiquitin ligase-USP15 pathway governs the destruction of neurofilament proteins. Proc Natl Acad Sci U S A, 120(45):e2306395120(2023) [pubmed]

10.1073/pnas.2306395120;

submitter keyword: USP15, GAN,Gigaxonin, neurofilament

Thang Van Nguyen
contact affiliation	University of Missouri
contact email	nguyentv@health.missouri.edu
lab head
Thao Thi Nguyen
contact affiliation	University of Missouri-Columbia
contact email	tnguyen24@wisc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD042592
     1. Label: PRIDE project
     2. Name: The CRL3gigaxonin ubiquitin ligase-USP15 pathway governs the destruction of neurofilament proteins