Affinage

SYNJ2BP

Synaptojanin-2-binding protein · UniProt P57105

Length
145 aa
Mass
15.9 kDa
Annotated
2026-06-10
10 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYNJ2BP is an outer mitochondrial membrane protein with a cytosolic PDZ domain that functions as a tethering scaffold organizing endoplasmic reticulum-mitochondria contact sites (MAMs/wrappER) and regulates inter-organelle lipid, calcium, ATP, and ion flux (PMID:36457006, PMID:36197105). In mouse liver its expression sets the extent of wrappER-mitochondria contacts, and its loss disrupts hepatic lipid flux, causing lipid droplet accumulation, increased VLDL/triglyceride secretion, and elevated mitochondrial fatty acid respiration (PMID:36457006). Genetic gain- and loss-of-function show SYNJ2BP bidirectionally controls MAM number: it raises ER ATP and calcium supply and relieves ER stress to support secretory protein folding, including lentiviral Env production (PMID:36197105), and it promotes the NLRX1-SLC39A7 complex to maintain mitochondrial Zn2+ homeostasis and prevent cell senescence (PMID:38158052). Through its PDZ domain SYNJ2BP engages C-terminal PDZ-binding motifs of partner proteins, recruiting the cell adhesion molecule TMIGD1 to mitochondria (PMID:32303178) and binding the activated somatostatin receptor SST2A; together with GRK2 (which binds its C-terminus) it promotes GRK-dependent receptor phosphorylation, internalization, and ERK1/2 activation (PMID:33313679). SYNJ2BP also acts as a negative regulator of activin/ActRII transcriptional signaling and a driver of breast cancer phenotypes, promoting lysosomal/autophagic PTEN degradation that activates PI3K/AKT/GSK3β-SNAI1 signaling and EMT (PMID:19349195, PMID:29163781). Dysregulated SYNJ2BP-dependent MAM remodeling is implicated in motor neuron disease, where elevated SYNJ2BP increases ER-mitochondria contacts and impairs mitochondrial oxidative function (PMID:35907632).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 Medium

    Established the first functional role of SYNJ2BP (ARIP2) as a PDZ-domain protein that binds activin type II receptors and tunes activin transcriptional output, framing it as a signaling regulator rather than a passive scaffold.

    Evidence Co-IP, reciprocal RNAi/overexpression, and transcriptional reporters in breast cancer cell lines

    PMID:19349195

    Open questions at the time
    • No structural mapping of the ActRII-PDZ interaction
    • Did not connect activin regulation to mitochondrial localization
  2. 2017 Medium

    Defined a mechanism for SYNJ2BP in cancer by showing it drives lysosomal/autophagic PTEN degradation to activate PI3K/AKT and EMT, linking it to metastasis.

    Evidence Overexpression/RNAi, PTEN-autolysosome colocalization, LC3-II/p62 and p-AKT Westerns, LY294002 rescue, and mouse metastasis model

    PMID:29163781

    Open questions at the time
    • Direct biochemical link between SYNJ2BP and PTEN not shown
    • How a mitochondrial protein routes PTEN to lysosomes unexplained
  3. 2020 Medium

    Showed SYNJ2BP uses its PDZ domain to bind a C-terminal PDZ-binding motif (in TMIGD1) and can recruit partners to mitochondria, establishing the molecular grammar of its scaffolding.

    Evidence Reciprocal Co-IP, domain-deletion mutants, and subcellular localization in renal epithelial cells

    PMID:32303178

    Open questions at the time
    • Functional consequence of TMIGD1 recruitment to mitochondria undefined
    • Reported plasma membrane localization not reconciled with mitochondrial role
  4. 2021 Medium

    Extended the PDZ-scaffold model to GPCR regulation, showing agonist-dependent binding to SST2A plus GRK2 recruitment drives receptor phosphorylation, internalization, and ERK activation.

    Evidence Unbiased PDZ screen, Co-IP, internalization assays, GRK2 interaction mapping, and cAMP/ERK readouts

    PMID:33313679

    Open questions at the time
    • Whether GPCR scaffolding occurs at mitochondria or plasma membrane unresolved
    • No structural basis for GRK2 binding to the SYNJ2BP C-terminus
  5. 2022 Medium

    Demonstrated SYNJ2BP is a bidirectional determinant of MAM number whose contacts supply ATP and calcium to the ER, relieve ER stress, and support secretory protein folding.

    Evidence CRISPR knockout and overexpression in HEK293T, EM MAM quantification, ATP/calcium and ER-stress assays, and viral Env folding readouts

    PMID:36197105

    Open questions at the time
    • ER-side tethering partner not identified
    • Quantitative stoichiometry of contact formation unknown
  6. 2022 High

    Provided the strongest in vivo evidence that SYNJ2BP sets wrappER-mitochondria contact extent and thereby governs hepatic lipid flux and VLDL secretion.

    Evidence AAV8 liver-specific knockdown with quantitative EM morphometry, proteomics, and lipid analysis in normal and ob/ob mice

    PMID:36457006

    Open questions at the time
    • Molecular partners forming wrappER contacts in liver not defined
    • Mechanism linking contact loss to altered lipid metabolism incomplete
  7. 2022 Medium

    Implicated SYNJ2BP-driven MAM remodeling in neurodegeneration, showing elevated levels alter mitochondrial distribution and impair oxidative function in patient motor neurons.

    Evidence iPSC-derived motor neurons from SBMA/ALS4 patients, proteomics, knockdown, mitochondrial function assays, and post-mortem tissue

    PMID:35907632

    Open questions at the time
    • Whether SYNJ2BP elevation is causal or compensatory in disease unclear
    • Upstream regulator of SYNJ2BP upregulation unknown
  8. 2022 Medium

    Showed SUMOylation at K107 controls localization of the SYNJ2BP-COX16 fusion and couples it to DRP1-driven mitochondrial fission and bioenergetics in cancer.

    Evidence K107R mutagenesis, fractionation, Co-IP for DRP1/UBC9, DRP1-S616 phospho-Westerns, Mdivi-1 rescue, and in vivo tumor models

    PMID:35998797

    Open questions at the time
    • Findings concern the SYNJ2BP-COX16 fusion, not wild-type SYNJ2BP
    • Whether native SYNJ2BP is SUMOylated at K107 not established
  9. 2023 Medium

    Connected SYNJ2BP-organized MAMs to mitochondrial zinc homeostasis via the NLRX1-SLC39A7 complex, defining an anti-senescence role in disc cells.

    Evidence Overexpression in nucleus pulposus cells, NLRX1-SLC39A7 Co-IP, Zn2+ measurement, senescence assays, and disc rejuvenation model

    PMID:38158052

    Open questions at the time
    • Whether SYNJ2BP directly binds NLRX1/SLC39A7 not shown
    • Generality of Zn2+ regulation beyond disc cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The ER-side tethering partner(s) of SYNJ2BP and how a single PDZ scaffold integrates ER-mitochondria contact formation with GPCR, activin, and PTEN signaling remain unresolved.
  • No defined ER membrane binding partner for the tether
  • No structural model of the PDZ domain bound to its physiological ligands
  • Unclear which functions reflect mitochondrial versus plasma membrane pools

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1430728 Metabolism 1
Partners
ACVR2ACOX16DNM1LGRK2SSTR2TMIGD1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Human ARIP2 (SYNJ2BP) contains a PDZ domain and interacts specifically with activin type II receptors (ActRIIs); overexpression reduces activin-induced transcriptional activity and enhances cell proliferation, while RNAi knockdown enhances activin signaling and reduces proliferation, establishing SYNJ2BP as a negative regulator of activin/ActRII signaling. Co-immunoprecipitation, RNAi knockdown, overexpression, transcriptional reporter assays in MCF-7 and MDA-MB-231 cells Cytokine Medium 19349195
2017 SYNJ2BP promotes degradation of PTEN via the lysosome/autophagy pathway (not proteasome), evidenced by co-localization of PTEN with autolysosomes and increased LC3-II and p62, leading to activation of PI3K/AKT/GSK3β signaling, nuclear accumulation of SNAI1, and EMT-driven metastasis in breast cancer. Overexpression and RNAi silencing, co-localization immunofluorescence, Western blotting for LC3-II/p62/p-AKT/p-GSK3β/SNAI1/E-cadherin, PI3K inhibitor (LY294002) rescue, in vivo mouse metastasis model Oncotarget Medium 29163781
2020 SYNJ2BP, an outer mitochondrial membrane protein with a PDZ domain, physically interacts with the cell adhesion molecule TMIGD1 via its PDZ domain binding the C-terminal PDZ-binding motif of TMIGD1, and can actively recruit TMIGD1 to mitochondria; SYNJ2BP localizes to both mitochondria and the plasma membrane. Co-immunoprecipitation, domain-deletion mutants, subcellular fractionation/immunofluorescence localization in renal epithelial cells BMC molecular and cell biology Medium 32303178
2021 SYNJ2BP interacts with somatostatin receptor 2A (SST2A) in an agonist-dependent manner requiring the PDZ-binding motif of SST2A; SYNJ2BP overexpression enhances ligand-stimulated receptor internalization by interacting with GRK2 (via the C-terminus of SYNJ2BP) and promoting GRK-dependent phosphorylation of SST2A, which is required for optimal agonist-stimulated ERK1/2 activation but does not affect cAMP suppression. Unbiased PDZ domain screen, Co-immunoprecipitation, receptor internalization assays, GRK2 interaction mapping, cAMP and ERK1/2 signaling assays, overexpression in cell lines Endocrinology Medium 33313679
2022 The fusion protein SYNJ2BP-COX16 is SUMOylated at K107; this SUMOylation regulates its mitochondrial subcellular localization. SUMOylated SYNJ2BP-COX16 recruits DRP1 to mitochondria, promotes UBC9 binding to DRP1 to enhance DRP1 SUMOylation and phosphorylation at S616, thereby inducing mitochondrial fission and increasing ATP production and COX activity to drive breast cancer proliferation and metastasis. SUMOylation site mutagenesis (K107R), subcellular fractionation/localization, Co-IP for DRP1/UBC9 interaction, DRP1 phosphorylation Western blotting, Mdivi-1 DRP1 inhibitor rescue, in vivo tumor models Cancer letters Medium 35998797
2022 Synj2bp expression in mouse liver positively correlates with the extent of wrappER-mitochondria contacts; AAV8-mediated liver-specific silencing of Synj2bp reduces wrappER-mitochondria contacts by ~50%, causing hepatic dyslipidemia (lipid droplet accumulation, increased VLDL/triglyceride secretion, reduced ApoE expression, increased mitochondrial fatty acid respiration), establishing Synj2bp as a regulator of ER-mitochondria tethering that controls hepatic lipid flux. AAV8 liver-specific knockdown, quantitative EM morphometry, proteomics, lipid analysis in normal and ob/ob mice Biology direct High 36457006
2022 Elevated SYNJ2BP in iPSC-derived motor neurons from SBMA and ALS4 patients alters cellular distribution of mitochondria and increases mitochondrial-ER membrane contact sites; decreasing SYNJ2BP levels improves mitochondrial oxidative function in diseased motor neurons. iPSC-derived motor neurons, proteomic analysis, SYNJ2BP knockdown, mitochondrial function assays, patient post-mortem tissue analysis Neurobiology of disease Medium 35907632
2022 SYNJ2BP is a key component of MAM (mitochondria-associated ER membrane); SYNJ2BP knockout reduces MAM number, while overexpression increases MAM formation. Increased MAMs provide more ATP and calcium ions to the ER and reduce ER stress, thereby improving lentiviral (EIAV and HIV) Env protein folding and production. SYNJ2BP knockout HEK293T cells (CRISPR), overexpression, EM quantification of MAMs, ATP/calcium measurement, ER stress assays, viral infectivity assays Journal of virology Medium 36197105
2023 SYNJ2BP overexpression in nucleus pulposus cells facilitates MAM contact organization and promotes NLRX1-SLC39A7 complex formation, thereby maintaining mitochondrial Zn2+ homeostasis and preventing NP cell senescence; SYNJ2BP loss is a pathological feature of intervertebral disc degeneration associated with MAM disruption and mitochondrial Zn2+ overload. Overexpression in NP cells, sequencing/proteomics of degenerative model, NLRX1-SLC39A7 complex co-immunoprecipitation, Zn2+ measurement, cell senescence assays, disc rejuvenation model Free radical biology & medicine Medium 38158052

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 SYNJ2BP promotes the degradation of PTEN through the lysosome-pathway and enhances breast tumor metastasis via PI3K/AKT/SNAI1 signaling. Oncotarget 24 29163781
2022 SUMOylation of SYNJ2BP-COX16 promotes breast cancer progression through DRP1-mediated mitochondrial fission. Cancer letters 22 35998797
2020 The mitochondrial outer membrane protein SYNJ2BP interacts with the cell adhesion molecule TMIGD1 and can recruit it to mitochondria. BMC molecular and cell biology 21 32303178
2022 Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis. Biology direct 17 36457006
2016 SYNJ2BP inhibits tumor growth and metastasis by activating DLL4 pathway in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 14 27440153
2022 Altered SYNJ2BP-mediated mitochondrial-ER contacts in motor neuron disease. Neurobiology of disease 12 35907632
2021 The PDZ Domain Protein SYNJ2BP Regulates GRK-Dependent Sst2A Phosphorylation and Downstream MAPK Signaling. Endocrinology 8 33313679
2009 Identification and characterization of human ARIP2 and its relation to breast cancer. Cytokine 8 19349195
2022 SYNJ2BP Improves the Production of Lentiviral Envelope Protein by Facilitating the Formation of Mitochondrion-Associated Endoplasmic Reticulum Membrane. Journal of virology 7 36197105
2023 SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis. Free radical biology & medicine 6 38158052

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