NOL10

NOL10 (PQBP5) is a nucleolar WD40-repeat protein central to 40S ribosomal subunit biogenesis and to the structural integrity of the nucleolus (PMID:27599843, PMID:36599853). It assembles into a salt-stable trimeric "ANN" complex with AATF/Che-1 and NGDN, with its WD40 repeats mediating complex formation and all three subunits showing mutual dependence for stability; this complex drives 18S rRNA maturation through pre-rRNA cleavage at the 5'ETS and ITS1 sites (PMID:27599843). As an intrinsically disordered protein, NOL10 constitutes the skeletal granule meshwork of the granular component of the nucleolus, remaining nucleolar under osmotic stress and serving as an anchor for reassembly of dispersed nucleolar proteins; its sequestration by polyglutamine disease proteins depletes functional NOL10 and produces nucleolar deformity (PMID:36599853). Consistent with this scaffolding role, NOL10 localizes to the granular component and exhibits very low mobility indicative of tight association with large processome-related complexes (PMID:24754225). WD-repeat integrity is essential for these functions: a homozygous p.Asn228His variant causes nucleoplasmic mislocalization, loss of AATF/NGDN binding, impaired 40S maturation, reduced polysome content, and G0/G1 arrest with increased cell death, defining NOL10 as the basis of a human ribosomopathy (PMID:41093997). NOL10 expression is regulated through a 2p25 risk allele that enhances USF1 binding to promote cell-cycle progression in prostate cancer (PMID:41062477), and it is a dependency of NUP98::DDX10 leukemia, binding the DDX10 moiety to regulate serine biosynthesis and ATF4 mRNA stability (PMID:40263434).

1. 2014 Medium

   Before its complex partners were known, it was unclear whether NOL10 was a transient or core nucleolar factor; live-cell dynamics established it as a low-mobility scaffold of large processome-related complexes.

   Evidence GFP-NOL10 FRAP and pharmacological rRNA transcription inhibition in HeLa cells

   PMID:24754225

   Open questions at the time

   • Did not identify the protein partners conferring low mobility
   • No direct rRNA processing readout
2. 2016 High

   Established the molecular partnership and biochemical function of NOL10 by defining the ANN complex and its requirement for pre-rRNA processing, answering how NOL10 contributes to 40S biogenesis.

   Evidence Reciprocal Co-IP, WD40 domain-mapping mutagenesis, siRNA depletion with Northern/pulse-chase rRNA processing analysis

   PMID:27599843

   Open questions at the time

   • Atomic structure of the trimeric complex not resolved
   • Order of assembly onto pre-rRNA undefined
3. 2023 High

   Resolved why NOL10 behaves as a stable scaffold rather than a phase-separating component, identifying it as the intrinsically disordered granular-component meshwork that anchors nucleolar reassembly and whose sequestration drives polyQ disease pathology.

   Evidence HS-AFM, super-resolution, CLEM, droplet and thermal shift assays, osmotic stress imaging, and in vitro/in vivo polyglutamine sequestration

   PMID:36599853

   Open questions at the time

   • How the meshwork interfaces with the ANN ribosome-biogenesis function not integrated
   • Mechanism of stress-resistant retention at molecular level unresolved
4. 2025 Medium

   Linked NOL10 to human disease by showing a WD-repeat point mutation abolishes localization, partner binding, and 40S maturation, establishing WD-domain integrity as the determinant of NOL10 function in patients.

   Evidence Exome sequencing, ΔΔG modeling, immunofluorescence, Co-IP, polysome profiling, cell cycle and death assays in patient fibroblasts

   PMID:41093997

   Open questions at the time

   • Single case
   • Spectrum of clinical phenotypes and additional alleles unknown
5. 2025 Medium

   Extended NOL10 beyond housekeeping ribosome biogenesis into oncogenic dependency, showing it cooperates with the NUP98::DDX10 fusion to control serine biosynthesis and ATF4 mRNA stability in leukemia.

   Evidence Co-IP interaction mapping to a 24-aa DDX10 region, Nol10 loss-of-function mouse leukemia model with survival readout, metabolic and ATF4 mRNA stability assays

   PMID:40263434

   Open questions at the time

   • Single lab
   • Mechanism by which NOL10 stabilizes ATF4 mRNA undefined
6. 2025 Medium

   Identified a transcriptional regulatory axis controlling NOL10 levels, connecting a GWAS risk allele to USF1-driven NOL10 expression and prostate cancer cell-cycle progression.

   Evidence SNPs-seq, allele-specific proteomic capture, NOL10 knockdown/overexpression with cell cycle pathway analysis

   PMID:41062477

   Open questions at the time

   • Direct cell-cycle effectors downstream of NOL10 not defined
   • Single lab
7. 2025 Low

   Suggested a conserved nucleolar stress-surveillance role via the fission yeast ortholog Enp2/NOL10 in rDNA silencing.

   Evidence Co-IP of RiboCop-Enp2-RNase H1 complex, ChIP, and genetic mutant analysis in fission yeast (preprint)

   PMID:41000809

   Open questions at the time

   • Preprint, yeast ortholog only
   • Complex not reconstituted and human relevance unestablished

• How NOL10's structural scaffolding role in the granular component is mechanistically coupled to its ANN-complex pre-rRNA processing activity, and how this dual function is co-opted across distinct cancers, remains unresolved.
• No integrated structural model of NOL10 within both the meshwork and the processome
• Substrate selectivity of pre-rRNA cleavage undefined