NBR1 (Next to BRCA1 gene 1 protein) — review notes

UniProt: Q14596 (NBR1_HUMAN), 966 aa. HGNC:6746. Located head-to-head with BRCA1 at 17q21.

Domain architecture (UniProt features)

• PB1 domain (4–85): mediates self-oligomerization and heterodimerization with SQSTM1/p62 [PMID:12813044; PMID:19250911]. Asp-50 is required for p62 interaction.
• ZZ-type zinc finger (212–264): binds two Zn2+ ions (8 coordinating residues). Basis of GO:0008270 zinc ion binding.
• ATG8/LIR regions (542–636 and 727–738): LC3-interacting regions; Tyr-732 mutation abolishes ATG8-family binding PMID:19250911.
• UBA domain (913–957): binds K48- and K63-linked polyubiquitin; F929A abolishes ubiquitin binding [PMID:24692539, PMID:19427866].
• An Ig-like / FW region (Nbr1_FW, ~365–485; PDB 4OLE).

Core function: ubiquitin-binding selective autophagy receptor

NBR1 is a ubiquitin-binding autophagy cargo receptor that, like its functional partner SQSTM1/p62, bridges ubiquitinated cargo to ATG8/LC3 on the forming autophagosome.
- PMID:19250911 — NBR1 contains PB1, ZZ, two LIR/ATG8-binding regions, and a UBA domain; interacts with SQSTM1, MAP1LC3A/B/C, GABARAP, GABARAPL1, GABARAPL2; required for autophagosomal degradation of ubiquitinated substrates; Asp-50 (p62 binding) and Tyr-732 (ATG8 binding) mutants characterized.
- PMID:19427866. Also binds USP8 and p14/Robld3 (endosomal trafficking).
- PMID:24692539 — F929A complete loss of ubiquitin binding; structural basis of UBA-Ub binding. (Not cached; verified via PubMed and UniProt features.)
- PMID:34471133 — in vitro reconstitution; NBR1 (with p62/TAX1BP1) drives ubiquitin condensate formation and autophagy initiation. Interacts with TAX1BP1. full_text_available: true.
- PMID:33226137 — receptor-mediated clustering of FIP200; NBR1 flux used as a selective-autophagy readout; NBR1 interacts with TAX1BP1.

Aggrephagy / protein aggregation

• PMID:24879152 — NBR1 promotes formation of ubiquitinated protein aggregates; GSK3A phosphorylation at Thr-586 inhibits this; relevant to inclusion body myositis. Supports aggrephagy (GO:0035973) and the dual aggregate-formation function noted in UniProt.
• PMID:20417604 — Alfy/WDFY3 scaffolds selective macroautophagy of aggregated proteins with p62/NBR1-positive proteins (NBR1 contextually a cargo partner). Background/context, NBR1 named in network.

Pexophagy (peroxisome turnover)

• Reactome R-HSA-9664873 "Pexophagy"; reactions R-HSA-9664867/9664880/9664881 (NBR1 binds MAP1LC3B; MAP1LC3B binds ATM:Ub-p-PEX5:SQSTM1:NBR1; NBR1 binds ATM:Ub-p-PEX5:SQSTM1). NBR1 (with p62) is the receptor for ubiquitinated PEX5 / peroxisomal membrane proteins → peroxisomal membrane localization (GO:0005778) is functionally grounded.

Innate immunity / antiviral selective autophagy

• PMID:35914352 — NBR1 binds IRF3 (both unphosphorylated and phosphorylated) and targets it for autophagic degradation; negatively regulates type I IFN. Interacts with IRF3; induced upon viral infection.
• PMID:33577621 — NBR1 recognizes ubiquitinated MAVS (K27-linked) and delivers it to autophagosomes; influenza PB1 hijacks this; NBR1 deficiency impairs MAVS degradation. Verified via PubMed (not cached). Supports antiviral innate immune response / selective autophagy roles.

SRBD1 clearance / cellular senescence

• PMID:38169523 — NBR1 interacts with SRBD1 and clears it via the autophagic-lysosomal pathway, retarding nucleus pulposus cell senescence. full_text_available: true.

FGFR / endosomal signaling

• PMID:19822672 — NBR1 as late endosomal protein in FGFR down-regulation. Supports late endosome (GO:0005770) localization.

Bone / osteoblast / MAPK (mouse-derived, ISS/IEA from Ensembl Compara to mouse ortholog P97432/Q501R9)

The negative regulation of osteoblast differentiation (GO:0045668), regulation of bone mineralization (GO:0030500), regulation of stress-activated MAPK cascade (GO:0032872) and MAPK binding (GO:0051019) annotations originate from BHF-UCL ISS and Ensembl Compara IEA, ultimately tracing to mouse Nbr1 work (Whitehouse et al.; p38 MAPK scaffold / osteoblast studies). NBR1 functions as a p38/MAPK scaffold and a truncated-NBR1 transgenic mouse shows increased bone mass via osteoblast effects. These are real but secondary/pleiotropic roles, supported only by ISS/IEA in human → KEEP_AS_NON_CORE.

Th2 / PB1 signalling adapter

• PMID:20808283 — T-cell-specific NBR1-deficient mice; impaired Th2 differentiation. PB1-domain adapter role; pleiotropic/immune developmental role (no GO term currently annotated from it; it is one of the IPI protein-binding sources).

Sarcomere / M band / titin

• UniProt: Cytoplasm, myofibril, sarcomere, M line (by similarity to mouse Q501R9). Interacts with titin/TTN and TRIM55 PMID:15802564. Basis of M band (GO:0031430) IEA-SubCell. Real but tissue-specific (cardiac/skeletal muscle) → KEEP_AS_NON_CORE.

Localization summary

Cytoplasm/cytosol (core), autophagosome/phagophore assembly site, lysosome (degraded there), late endosome, peroxisomal membrane (pexophagy), M band (muscle). Mitochondrion colocalization (GO:0005739, PMID:21296869) reflects Parkin-mitophagy context. Mitochondrial intermembrane space (GO:0005758, Ensembl IEA) and membrane (GO:0016020, HDA from NK-cell membrane proteome PMID:19946888) are low-confidence/generic.

Protein binding (IPI) sources

Many GO:0005515 protein binding annotations from interactome/specific studies: PMID:19250911 (SQSTM1, ATG8s), 19427866 (USP8, ubiquitin), 20010802 (Nix mitophagy context), 20368287 (PI3K-mTOR interactome), 20417604 (Alfy), 20562859 (autophagy network), 20808283 (Th2 PB1 adapter), 24879152 (GSK3), 25416956/33961781 (HuRI/BioPlex interactomes), 29568061 (MAC-tag), 30824926 (GSK3A/sperm), 34524948 (macroautophagy proximity interactome), 19822672 (Spred2/FGFR). All KEEP_AS_NON_CORE per "avoid bare protein binding" guideline; informative partners noted in reasons.

Key GO terms verified via QuickGO API

• GO:0035973 aggrephagy = "selective degradation of protein aggregates by macroautophagy"
• GO:0000425 pexophagy
• GO:0160247 autophagy cargo adaptor activity = "binding activity of a molecule that brings together a cargo, targeted for degradation via autophagy, to a phagophore" (the precise MF for an autophagy receptor)
• GO:0061753 substrate localization to autophagosome
• GO:0032480 negative regulation of type I interferon production
• GO:0140374 antiviral innate immune response