Affinage

NBAS

NBAS subunit of NRZ tethering complex · UniProt A2RRP1

Length
2371 aa
Mass
268.6 kDa
Annotated
2026-06-10
53 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NBAS is a moonlighting protein that operates in two largely separable cellular processes: ER-to-Golgi retrograde vesicular trafficking and nonsense-mediated mRNA decay (NMD) (PMID:26073778, PMID:21227923). In the trafficking arm, NBAS functions as a component of the syntaxin 18/NRZ tethering complex, where it stabilizes its interaction partner p31/USE1—loss of NBAS function reduces p31 protein levels even when NBAS itself is preserved, making p31 a sensitive functional readout of NBAS activity (PMID:26073778, PMID:30622725, PMID:35433172). The syntaxin 18 complex containing NBAS is thermally susceptible, and its Sec39-domain variants destabilize the protein under elevated temperature while disturbing vesicle tethering, providing the molecular basis for fever-triggered ER stress and acute liver failure (PMID:26541327, PMID:33707149). Defective retrograde transport in NBAS-mutant fibroblasts impairs collagen secretion and reduces expression of the bone regulator MGP, linking NBAS to skeletal phenotypes (PMID:33707149, PMID:32768688). In parallel, NBAS is required for NMD: its depletion stabilizes PTC-containing transcripts and, together with DHX34, co-regulates a conserved set of endogenous NMD targets including transcripts encoding NMD factors themselves, marking NBAS as part of an autoregulatory feedback loop alongside core factors UPF1 and SMG5/6 (PMID:21227923, PMID:23828042). NBAS also supports immune cytotoxicity, being required in NK cells for lytic granule polarization and degranulation through a Golgi-associated vesicular transport mechanism (PMID:35902954, PMID:34386911). Biallelic NBAS variants cause a spectrum of human disease in which distinct protein domains correlate with non-overlapping clinical subgroups (PMID:31761904).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2011 High

    Established that NBAS is not solely a trafficking protein but is functionally required for nonsense-mediated mRNA decay, an unexpected second role.

    Evidence Morpholino knockdown in zebrafish embryos with NMD reporter assays and phenotypic comparison to core NMD factors

    PMID:21227923

    Open questions at the time
    • Does not define the biochemical step in NMD at which NBAS acts
    • No human cell validation in this study
  2. 2013 High

    Defined NBAS as a co-regulator with DHX34 of a conserved NMD autoregulatory feedback loop, placing it within the regulatory architecture rather than just substrate degradation.

    Evidence Microarray profiling after RNAi depletion of NBAS or DHX34 across human cells, zebrafish, and C. elegans

    PMID:23828042

    Open questions at the time
    • Does not establish direct physical interaction of NBAS with DHX34 or UPF1
    • Mechanism connecting NMD role to trafficking role unresolved
  3. 2015 Medium

    Identified NBAS as a component of ER-to-Golgi retrograde transport whose loss destabilizes its partner p31/USE1, anchoring the trafficking function.

    Evidence Immunoblot of patient fibroblasts with biallelic loss-of-function mutations

    PMID:26073778

    Open questions at the time
    • Direct binding interface between NBAS and p31 not mapped
    • Stoichiometry within the syntaxin 18/NRZ complex not defined
  4. 2015 Medium

    Explained fever-triggered acute liver failure mechanistically by showing the NBAS-containing syntaxin 18 complex is thermally susceptible and that vesicle tethering fails.

    Evidence Heat-sensitivity and vesicle tethering assays in patient fibroblasts

    PMID:26541327

    Open questions at the time
    • Which subunit confers thermal lability not isolated
    • Liver-specific vulnerability not explained at cellular level
  5. 2019 Low

    Linked distinct NBAS protein domains to non-overlapping clinical subgroups, implying domain-specific molecular functions.

    Evidence Computational structure modeling with genotype-phenotype correlation across 110 patients

    PMID:31761904

    Open questions at the time
    • No direct biochemical validation of domain-specific function
    • Structural model not experimentally confirmed
  6. 2019 Medium

    Refined the functional readout for NBAS deficiency by showing p31 reduction occurs even when NBAS protein is preserved, indicating p31 stability strictly depends on NBAS.

    Evidence Western blot of NBAS and p31 in patient fibroblasts including missense-variant cases

    PMID:30622725

    Open questions at the time
    • Does not determine whether NBAS directly protects p31 from degradation
    • Generality across all variant classes not established
  7. 2020 Medium

    Connected NBAS retrograde transport function to collagen secretion and bone homeostasis via reduced MGP expression and impaired secretion.

    Evidence Thermostability, MGP expression, and collagen secretion assays in patient fibroblasts (two studies)

    PMID:32768688 PMID:33707149

    Open questions at the time
    • Mechanism by which retrograde defect lowers collagen secretion not resolved
    • MGP downregulation pathway not mapped
  8. 2021 Medium

    Demonstrated an NK cell-intrinsic role for NBAS in cytotoxic granule release, reversible by IL-2 pre-activation.

    Evidence Immunophenotyping and CD107a degranulation assays with IL-2 rescue in patient NK cells

    PMID:34386911

    Open questions at the time
    • Molecular step in degranulation requiring NBAS not defined
    • Single-lab patient cohort
  9. 2022 Medium

    Placed NBAS upstream of NK degranulation through a Golgi-associated retrograde transport mechanism affecting lytic granule polarization.

    Evidence shRNA knockdown in IMC-1 NK cell line with immunofluorescence quantification of granules near Golgi

    PMID:35902954

    Open questions at the time
    • Direct trafficking cargo for granule polarization not identified
    • Link to the syntaxin 18 complex in NK cells not shown
  10. 2022 High

    Revealed a GEF activity for the NBAS ortholog SMGL-1 toward RAB-8 driving unconventional protein secretion, the most direct biochemical mechanism yet for an NBAS-family protein.

    Evidence C. elegans genetics, in vitro RAB-8 GEF assay, co-localization, and epistasis with NRZ component CZW-1/ZW10

    PMID:35604368

    Open questions at the time
    • Whether human NBAS retains RAB-8 GEF activity not demonstrated
    • Relationship between GEF function and retrograde tethering not integrated
  11. 2023 Medium

    Showed a specific missense variant destabilizes NBAS and induces ROS, apoptosis, and ER stress, supporting a stress-driven pathomechanism.

    Evidence Ectopic expression of wild-type versus p.C448R NBAS with ROS, apoptosis, and ER stress marker assays

    PMID:37055399

    Open questions at the time
    • Overexpression system may not reflect physiological context
    • Causality between ER stress and tissue phenotype not established
  12. 2023 Low

    Documented co-localization of NBAS with UPF1 and with p31 in lung epithelial cells, and association with SARS-CoV-2 proteins.

    Evidence Immunofluorescence co-localization in infected Calu3 cells

    PMID:36768954

    Open questions at the time
    • Single co-localization experiment without functional consequence
    • No reciprocal validation of NBAS-UPF1 physical interaction
  13. 2025 Low

    Provided a structural rationale for thermal instability by simulating Sec39-domain variants under fever-range temperature.

    Evidence Molecular dynamics simulation of wild-type and mutant Sec39 domain at 37°C and 42°C

    PMID:40680151

    Open questions at the time
    • Computational only, no biochemical thermostability measurement
    • Predicted conformational changes not experimentally confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NBAS coordinates or partitions its trafficking and NMD functions, and whether human NBAS possesses the RAB-8 GEF activity seen in its ortholog, remains unresolved.
  • No reconstituted human NBAS GEF assay
  • Mechanistic link between NMD and retrograde transport roles undefined
  • Tissue-specific basis of distinct clinical subgroups not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-8953854 Metabolism of RNA 2
Partners
DHX34RAB8AUPF1USE1ZW10
Complex memberships
syntaxin 18/NRZ complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 NBAS protein is involved in retrograde vesicular transport between the endoplasmic reticulum and Golgi; loss-of-function mutations reduce protein levels of NBAS and its interaction partner p31 (USE1), as shown by immunoblot analysis of patient fibroblasts. Immunoblot analysis of patient-derived fibroblasts; genetic identification of biallelic loss-of-function mutations American journal of human genetics Medium 26073778
2015 The syntaxin 18 complex (of which NBAS is a component) is thermally susceptible, providing the molecular basis for fever-triggered acute liver failure episodes in NBAS deficiency; patient fibroblasts showed increased sensitivity to high temperature at both protein and functional levels, and a disturbed tethering of vesicles indicating a defect in ER-to-Golgi retrograde transport. Functional studies on patient fibroblasts: heat sensitivity assays, vesicle tethering assays Journal of inherited metabolic disease Medium 26541327
2011 Zebrafish NBAS (NAG/NBAS) is required for nonsense-mediated mRNA decay (NMD): morpholino-induced depletion of zebrafish Nbas results in failure to degrade PTC-containing mRNAs, severe developmental defects, and reduced embryonic viability, phenotypes similar to those caused by depletion of core NMD factors Upf1, Smg-5, and Smg-6. Morpholino knockdown in zebrafish embryos; NMD reporter assays for PTC-containing mRNA degradation; phenotypic analysis Nucleic acids research High 21227923
2013 DHX34 and NBAS co-regulate a large set of endogenous NMD target transcripts in human cells, zebrafish, and C. elegans; depletion of either factor stabilizes transcripts encoding NMD factors themselves, demonstrating participation in a conserved NMD negative feedback autoregulatory loop. NMD also modulates cellular stress response and membrane trafficking pathways. Microarray expression profiling after RNAi-mediated depletion of DHX34 or NBAS in human cells, zebrafish embryos, and C. elegans; comparison with core NMD factor depletions Nucleic acids research High 23828042
2022 NBAS deficiency impairs NK cell cytotoxic degranulation: knockdown of NBAS in the NK cell line IMC-1 via shRNA resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus, placing NBAS upstream of the degranulation pathway in a Golgi-to-ER retrograde transport context. shRNA knockdown of NBAS in NK cell line (IMC-1); immunofluorescence for lytic granule polarization; quantification of cytotoxic vesicles near Golgi Journal of hematology & oncology Medium 35902954
2021 NBAS-deficient patient NK cells show reduced absolute numbers of mature CD56dim NK cells, lower activation and degranulation in response to K562 target cells; this functional impairment was reversible upon pre-activation with IL-2 in vitro, indicating an NK cell-intrinsic role for NBAS in cytotoxic granule release. Multi-parametric immunophenotyping; functional degranulation assays (CD107a) with K562 target cells; IL-2 rescue experiment in patient-derived NK cells Journal of clinical immunology Medium 34386911
2022 C. elegans SMGL-1 (NBAS ortholog) acts as a guanine nucleotide exchange factor (GEF) for RAB-8, activating RAB-8 to drive unconventional Golgi-bypassing protein secretion (UPS) of integral membrane proteins. SMGL-1 resides in the ER-Golgi intermediate compartment and adjacent RAB-8-positive structures, and its localization there requires the NRZ complex component CZW-1/ZW10. C. elegans genetics; GEF activity assay for RAB-8; live imaging and co-localization; loss-of-function (smgl-1 and rab-8 mutants); epistasis with NRZ complex (czw-1/ZW10) The Journal of cell biology High 35604368
2019 The NBAS protein contains structurally and functionally distinct domains (β-propeller, Sec39, C-terminal) that correspond to distinct clinical subgroups; protein modeling refined the β-propeller domain structure, and missense variants/in-frame deletions in different domains produce non-overlapping clinical phenotypes (combined, ILFS2, SOPH), implying domain-specific molecular functions. Computational protein structure prediction/modeling; genotype-phenotype correlation analysis in 110 patients with biallelic variants Genetics in medicine Low 31761904
2020 Mutant NBAS protein (carrying variants in the Sec39 domain) is thermally unstable and reduces expression of MGP (a regulator of bone homeostasis) in patient fibroblasts; additionally, reduced collagen secretion was observed, suggesting NBAS variants impair ER-to-Golgi retrograde transport needed for collagen secretion. Functional studies in patient fibroblasts: protein stability assays at elevated temperature, MGP expression analysis, collagen secretion assay Molecular genetics and metabolism Medium 33707149
2020 A novel NBAS missense substitution causes altered Golgi-to-ER retrograde vesicular trafficking and reduced collagen secretion in patient fibroblasts, directly linking NBAS function to collagen secretion and bone phenotype. In vitro functional studies on patient fibroblasts: vesicular trafficking assay; collagen secretion assay Bone Medium 32768688
2019 Reduced protein levels of NBAS interaction partner p31 (USE1) serve as a functional biomarker for NBAS deficiency; Western blot of patient fibroblasts showed reduced p31 levels even in cases where NBAS protein itself was not decreased (two missense variants), demonstrating that p31 stability depends on NBAS function. Western blotting for NBAS and p31 protein levels in patient-derived fibroblasts Human genome variation Medium 30622725
2022 p31 (USE1) protein levels were reduced in all three patient families tested by Western blotting, including an individual with two missense variants where NBAS protein levels were preserved, further confirming that p31 stability is dependent on NBAS function and that p31 level is a more sensitive functional readout than NBAS level alone. Western blotting for NBAS and p31 protein levels in patient fibroblasts from three families JIMD reports Medium 35433172
2023 A missense variant p.C448R in NBAS produces a protein with reduced mRNA and protein expression upon ectopic expression compared to wild-type, and induces increased intracellular reactive oxygen species, apoptosis, and ER stress marker expression in cultured cells, suggesting the mutant protein causes ER stress and is less stable than wild-type. Ectopic overexpression of wild-type vs. p.C448R NBAS; RT-qPCR and Western blot for expression; ROS assay; apoptosis assay; Western blot for ER stress markers Human genome variation Medium 37055399
2025 Molecular dynamics simulations of NBAS Sec39 domain missense variants (p.Leu744Pro and p.Arg756Cys) demonstrate that wild-type NBAS is thermostable at both 37°C and 42°C, while mutant NBAS shows pronounced conformational fluctuations, disrupted hydrogen-bonding networks, and secondary structural reorganization specifically under thermal stress (42°C), providing a structural mechanism for fever-triggered acute liver failure. Molecular dynamics simulation (MDS) of wild-type and mutant NBAS Sec39 domain at 37°C and 42°C Human molecular genetics Low 40680151
2023 NBAS and UPF1 proteins co-localize in human lung epithelial cells (Calu3), and NBAS co-localizes with p31 (USE1); co-localization of NBAS with UPF1 and with p31 was not altered by SARS-CoV-2 infection within 24 h, and both NBAS and UPF1 were found to co-localize with SARS-CoV-2 S and N proteins. Immunofluorescence co-localization in SARS-CoV-2-infected Calu3 cells International journal of molecular sciences Low 36768954

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy. American journal of human genetics 99 26073778
2015 Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts. Journal of inherited metabolic disease 80 26541327
2013 DHX34 and NBAS form part of an autoregulatory NMD circuit that regulates endogenous RNA targets in human cells, zebrafish and Caenorhabditis elegans. Nucleic acids research 76 23828042
2015 NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina. American journal of medical genetics. Part A 58 26286438
2019 Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients. Genetics in medicine : official journal of the American College of Medical Genetics 56 31761904
2011 Dhx34 and Nbas function in the NMD pathway and are required for embryonic development in zebrafish. Nucleic acids research 56 21227923
2016 Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta. Bone 43 27789416
2015 Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: Confirmatory report in a sibship with very early onset, osteoporosis and developmental delay. European journal of medical genetics 36 26578240
2017 Novel NBAS mutations and fever-related recurrent acute liver failure in Chinese children: a retrospective study. BMC gastroenterology 30 28629372
2024 Disorders of vesicular trafficking presenting with recurrent acute liver failure: NBAS, RINT1, and SCYL1 deficiency. Journal of inherited metabolic disease 20 38279772
2019 Novel neuroblastoma amplified sequence (NBAS) mutations in a Japanese boy with fever-triggered recurrent acute liver failure. Human genome variation 20 30622725
2019 NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype-phenotype correlations. Human mutation 18 30825388
2020 NBAS disease: 14 new patients, a recurrent mutation, and genotype-phenotype correlation among 24 Chinese patients. Hepatology research : the official journal of the Japan Society of Hepatology 17 32812336
2017 NBAS mutations cause acute liver failure: when acetaminophen is not a culprit. Italian journal of pediatrics 17 28946922
2017 Targeted next‑generation sequencing reveals two novel mutations of NBAS in a patient with infantile liver failure syndrome‑2. Molecular medicine reports 16 29207168
2022 NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis. Journal of hematology & oncology 15 35902954
2021 NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency. Journal of clinical immunology 15 34386911
2018 Cryptic intronic NBAS variant reveals the genetic basis of recurrent liver failure in a child. Molecular genetics and metabolism 15 30558828
2018 SOPH Syndrome with Growth Hormone Deficiency, Normal Bone Age, and Novel Compound Heterozygous Mutations in NBAS. Fetal and pediatric pathology 15 30592236
2022 SMGL-1/NBAS acts as a RAB-8 GEF to regulate unconventional protein secretion. The Journal of cell biology 12 35604368
2020 A 34-year-old Japanese patient exhibiting NBAS deficiency with a novel mutation and extended phenotypic variation. European journal of medical genetics 12 32805445
2017 Foveal hypoplasia in short stature with optic atrophy and Pelger-Huët anomaly syndrome with neuroblastoma-amplified sequence (NBAS) gene mutation. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus 12 28115293
2020 Severe SOPH syndrome due to a novel NBAS mutation in a 27-year-old woman-Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades. American journal of medical genetics. Part A 10 32297715
2022 MEFV, IRF8, ADA, PEPD, and NBAS gene variants and elevated serum cytokines in a patient with unilateral sporadic Meniere's disease and vascular congestion over the endolymphatic sac. Journal of otology 8 35847575
2020 Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency. Bone 8 32768688
2020 Complex Multisystem Phenotype With Immunodeficiency Associated With NBAS Mutations: Reports of Three Patients and Review of the Literature. Frontiers in pediatrics 8 33042920
2021 Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations. Frontiers in pediatrics 7 33520894
2023 A novel variant in NBAS identified from an infant with fever-triggered recurrent acute liver failure disrupts the function of the gene. Human genome variation 6 37055399
2022 Distinct diagnostic trajectories in NBAS-associated acute liver failure highlights the need for timely functional studies. JIMD reports 6 35433172
2021 Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS Variants Leading to a Phenotype Similar to Odontochondrodysplasia. Frontiers in genetics 6 34149817
2024 Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease. Molecular genetics and metabolism 5 38244286
2022 Case report: A novel cause of acute liver failure in children: A combination of human herpesvirus-6 infection and homozygous mutation in NBAS gene. Journal of clinical laboratory analysis 5 35349761
2022 Characterization of a novel non-canonical splice site variant (c.886-5T>A) in NBAS and description of the associated phenotype. Molecular genetics & genomic medicine 5 36479642
2021 Characterization of a complex phenotype (fever-dependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants. Molecular genetics and metabolism 5 33707149
2021 NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Metabolic brain disease 5 34427841
2023 Modulation of NBAS-Related Functions in the Early Response to SARS-CoV-2 Infection. International journal of molecular sciences 4 36768954
2021 Resolution of recurrent pediatric acute liver failure with liver transplantation in a patient with NBAS mutation. Pediatric transplantation 3 34288298
2025 RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency. Molecular genetics and metabolism 2 40215727
2023 [Liver transplantation for the treatment of acute liver failure in 3 cases with NBAS gene deficiency and literature review]. Zhonghua er ke za zhi = Chinese journal of pediatrics 2 36594124
2019 Oculofacial alterations in NBAS-SOPH like mutations: Case report. European journal of ophthalmology 2 30845840
2016 [Population frequency and age of mutation G5741→A in gene NBAS which is a cause of SOPH syndrome in Sakha (Yakutia) Republic]. Genetika 2 29369590
2025 [Clinical features and genetic study of four cases of pediatric acute liver failure caused by NBAS gene variants]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 1 39606973
2025 [Clinical features and genetic analysis of three patients with Infantile liver failure syndrome type 2 due to variants of NBAS gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 39779337
2024 Autoimmune hemolytic anemia and thrombocytopenia in a Chinese patient with heterozygous NBAS mutations: Case report. Medicine 1 38517998
2024 Protein-Variant-Phenotype Study of NBAS Using AlphaFold in the Aspect of SOPH Syndrome. Proteins 1 39641476
2023 Pregnancy, delivery, and postpartum period in infantile liver failure syndrome type 2 due to variants in NBAS. JIMD reports 1 37151364
2021 Novel compound heterozygous variants in the NBAS gene in a child with osteogenesis imperfecta and recurrent acute liver failure. BMJ case reports 1 33542026
2021 Structural Uniqueness of the [Nb(As5)2]5- Cluster in the Zintl Phase Cs5NbAs10. The journal of physical chemistry. A 1 33998228
2019 Generation of an iPSC line from a patient with infantile liver failure syndrome 2 due to mutations in NBAS: DHMCi004-A. Stem cell research 1 30772683
2025 Novel compound heterozygous variants in NBAS underlying fever-dependent infantile liver failure syndrome type 2: potential implications of protein thermostability. Human molecular genetics 0 40680151
2025 Case Report: Hemophagocytic lymphohistiocytosis associated with NBAS gene variant and Epstein-Barr virus (EBV) infection. Frontiers in pediatrics 0 40894400
2025 Unveiling a novel NBAS mutation in common variable immunodeficiency: Expanding the genetic landscape of immunodeficiency disorders. Immunobiology 0 41862227
2024 Hemophagocytic Lymphohistiocytosis in Association With Neuroblastoma Amplified Sequence (NBAS) Gene Variants: A Report of a Rare Case. Cureus 0 39429260

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