Affinage

STBD1

Starch-binding domain-containing protein 1 · UniProt O95210

Length
358 aa
Mass
39.0 kDa
Annotated
2026-06-10
13 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STBD1 is a selective autophagy receptor for glycogen (glycophagy) that bridges glycogen cargo to the autophagy machinery and integrates glycogen metabolism with membrane-contact and metabolic signaling (PMID:21893048, PMID:39236246). Its C-terminal CBM20 carbohydrate-binding domain engages glycogen through two distinct oligosaccharide-binding sites (the conserved W293 being essential), while an N-terminal LIR/AIM motif (core residues W203, V206) selectively binds all six mammalian ATG8-family proteins and recruits the autophagy-initiation factor RB1CC1/FIP200 through its Claw domain, with both intact carbohydrate binding and ATG8 engagement required for productive glycophagy complex assembly (PMID:21893048, PMID:39236246). The CBM20 domain also mediates protein-protein contacts with glycogen-metabolic enzymes (glycogen synthase, glycogen debranching enzyme, and laforin) and is required for STBD1 stability, as carbohydrate-binding-deficient protein is rapidly degraded by the ubiquitin-proteasome system (PMID:24837458). STBD1 is an N-myristoylated ER-resident transmembrane protein that additionally localizes to ER-mitochondria contact sites (MAMs), where it controls ER-mitochondria apposition and mitochondrial morphology, and to lipid droplets, where it links glycogen and lipid-droplet metabolism (PMID:28137759, PMID:41105508). STBD1 is embedded in metabolic stress signaling: it is a direct AMPK substrate phosphorylated on Ser175 and acts upstream of AMPK to promote insulin sensitivity, it is induced via the PERK/UPR branch during ER stress to drive pro-survival glycogen clustering, and its loss in mice causes reduced hepatic glycogen, insulin resistance, and altered ER-mitochondria contacts (PMID:30772465, PMID:32958708, PMID:35691532, PMID:40001216).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2011 High

    Established that STBD1 is a cargo receptor for glycophagy by identifying the molecular handle linking it to the autophagy machinery, answering how glycogen is selectively delivered to lysosomes.

    Evidence Co-IP, AIM site-directed mutagenesis (W203, V206), and co-localization microscopy with GABARAPL1

    PMID:21893048

    Open questions at the time
    • Did not define the structural basis of ATG8 selectivity
    • Did not establish in vivo requirement for glycogen clearance
  2. 2013 Medium

    Tested whether STBD1 is the essential route for lysosomal glycogen delivery in muscle, showing it is dispensable in this tissue context and that redundant pathways exist.

    Evidence AAV-delivered Stbd1 shRNA in GAA-KO (Pompe) mice with histochemical and biochemical glycogen readouts

    PMID:23726947

    Open questions at the time
    • Negative result confined to skeletal muscle
    • Knockdown may have been incomplete
    • Did not address liver or other tissues
  3. 2014 Medium

    Defined the CBM20 domain as the dual-function module for glycogen recognition and stability, and identified its interactions with glycogen-metabolic enzymes, situating STBD1 within glycogen metabolism beyond autophagy.

    Evidence W293A mutagenesis, amylose pull-down, Co-IP with GS/GDE/laforin, proteasome inhibitor rescue and ubiquitination assays in COS/HepG2 cells

    PMID:24837458

    Open questions at the time
    • Functional consequence of enzyme interactions not resolved
    • Ubiquitin ligase responsible for degradation unidentified
    • Single-lab biochemistry
  4. 2017 High

    Identified the subcellular targeting code of STBD1 (myristoylation plus glycogen binding) and revealed a role at ER-mitochondria contacts, expanding its function beyond cargo recognition.

    Evidence Chemical myristoylation labeling, shRNA knockdown, myristoylation-deficient overexpression, fractionation and live-cell imaging in mouse cells

    PMID:28137759

    Open questions at the time
    • Mechanism by which STBD1 regulates contact-site spacing unknown
    • Link to glycophagy at MAMs not established
  5. 2019 Medium

    Placed STBD1 within AMPK signaling by identifying it as a direct phosphorylation substrate, raising the question of how this modification feeds back on its function.

    Evidence Analog-sensitive AMPK chemical-genetic screen, MS phosphopeptide identification, and phospho-Ser175-specific immunoblotting across tissues

    PMID:30772465

    Open questions at the time
    • Functional effect of Ser175 phosphorylation not determined
    • Directionality of AMPK-STBD1 relationship unresolved at this stage
  6. 2020 Medium

    Connected STBD1 to the ER stress response by showing it is a PERK/UPR-induced effector that drives pro-survival glycogen clustering, defining a stress-adaptive role.

    Evidence shRNA knockdown, overexpression, PERK inhibition, glycogen-structure imaging and apoptosis assays in mouse myoblasts

    PMID:32958708

    Open questions at the time
    • Molecular mechanism of glycogen clustering by STBD1 unknown
    • Relationship between clustering and glycophagy flux not resolved
  7. 2022 Medium

    Provided in vivo evidence linking STBD1's MAM function to systemic glucose homeostasis, showing loss causes insulin resistance and altered ER-mitochondria contacts.

    Evidence Stbd1-KO mice with glucose/insulin tolerance tests, insulin-signaling immunoblots, EM of contact sites, and lipidomics

    PMID:35691532

    Open questions at the time
    • Causal chain from MAM changes to insulin resistance not dissected
    • Tissue-specific contributions not separated
  8. 2024 High

    Resolved the structural basis of glycophagy by determining how the CBM20 domain reads glycogen via two oligosaccharide sites and how the LIR motif engages ATG8 proteins and recruits FIP200, defining the molecular logic of cargo-machinery coupling.

    Evidence X-ray crystallography of CBM20-maltotetraose and LIR/GABARAPL1 complexes, binding assays, and cell-based assays with LIR/CBM20 mutants

    PMID:39236246

    Open questions at the time
    • Stoichiometry of full glycophagy complex on glycogen particles not defined
    • How phosphorylation or myristoylation modulate these interactions not addressed
  9. 2025 Medium

    Extended STBD1 function to lipid-droplet biology, showing myristoylation-dependent LD targeting mediates glycogen-LD crosstalk and supports both glycophagy and lipophagy.

    Evidence BioID LD-proteome labeling, knockdown in vitro and in vivo, LD quantification, flux assays, lipidomics and myristoylation-mutant targeting in clear cell renal cell carcinoma

    PMID:41105508

    Open questions at the time
    • Direct LD-anchoring partners not identified
    • Generalizability beyond ccRCC unestablished
  10. 2025 Medium

    Resolved the directionality of the STBD1-AMPK relationship, placing STBD1 upstream as an AMPK activator that improves insulin sensitivity independently of its myristoylation and contact-site roles.

    Evidence Hepatocyte overexpression (including myristoylation-deficient mutant), AMPK phosphorylation and insulin-signaling assays, and mechanistic exclusion experiments

    PMID:40001216

    Open questions at the time
    • Mechanism by which STBD1 activates AMPK unknown
    • Relationship to Ser175 phosphorylation feedback not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How STBD1's distinct activities — glycophagy cargo selection, MAM regulation, LD targeting, and AMPK activation — are coordinated and selectively engaged in different tissues and metabolic states remains unresolved.
  • No unifying model connecting cargo-receptor and metabolic-signaling functions
  • Functional role of Ser175 phosphorylation undefined
  • Identity of the ubiquitin ligase controlling STBD1 turnover unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 2 GO:0060090 molecular adaptor activity 2 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0005739 mitochondrion 2 GO:0005783 endoplasmic reticulum 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
AMPKGABARAPL1GDEGSLAFORINRB1CC1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 STBD1 contains an Atg8-family interacting motif (AIM) with sequence (200)HEEWEMV(206) required for interaction with GABARAPL1; single point mutations of W203 or V206 within this AIM abolished co-localization of STBD1 with both overexpressed and endogenous GABARAPL1, establishing STBD1 as a cargo-binding receptor that delivers glycogen to lysosomes via a glycophagy pathway. Co-immunoprecipitation from cell extracts, site-directed mutagenesis of AIM residues, immunofluorescence co-localization microscopy Biochemical and biophysical research communications High 21893048
2017 Mouse STBD1 is N-myristoylated, an ER-resident transmembrane protein that also localizes to mitochondria-associated membranes (MAMs); N-myristoylation and glycogen binding are major determinants of its subcellular targeting. Overexpression of non-myristoylated STBD1 enhanced ER-mitochondria association and induced mitochondrial fragmentation, while shRNA-mediated Stbd1 silencing increased ER-mitochondria spacing and promoted mitochondrial fusion/interconnectivity. Chemical labeling for N-myristoylation detection, shRNA knockdown, overexpression of myristoylation-deficient mutant, live-cell imaging/immunofluorescence, subcellular fractionation Journal of cell science High 28137759
2014 The CBM20 carbohydrate-binding domain of STBD1 is required for amylose binding (conserved W293 is essential), protein stability (W293 mutant undergoes rapid proteasomal degradation), and protein-protein interactions with glycogen-associated proteins glycogen synthase (GS), glycogen debranching enzyme (GDE), and Laforin. STBD1 itself undergoes ubiquitination requiring its N-terminus. Interaction with GS increased during glycogenolysis, suggesting glycogen is not required to bridge this interaction. Site-directed mutagenesis (W293A), co-immunoprecipitation, carbohydrate-binding assay (amylose pull-down), proteasome inhibitor rescue, ubiquitination assay in COS cells, overexpression in HepG2 cells Bioscience reports Medium 24837458
2013 shRNA-mediated suppression of Stbd1 expression in GAA-knockout (Pompe disease) mice did not alter lysosomal glycogen accumulation in skeletal muscle, indicating that Stbd1 is not the sole or essential mediator of lysosomal glycogen delivery in this tissue context. AAV2/9-delivered Stbd1-specific shRNA in GAA-KO mice, histochemical and biochemical analysis of lysosomal glycogen content Molecular genetics and metabolism Medium 23726947
2019 AMPK phosphorylates STBD1 on Ser175 in multiple cell types and tissues, identifying STBD1 as a direct substrate of AMPK. Chemical genetic screen with analog-sensitive AMPK activator 991 in primary mouse hepatocytes, mass spectrometry identification of phosphorylated peptides, phospho-site-specific antibody immunoblotting Cellular signalling Medium 30772465
2024 Crystal structure of STBD1 CBM20 domain with maltotetraose revealed two distinct oligosaccharide-binding sites used for glycogen recognition. The STBD1 LIR motif selectively binds all six mammalian ATG8 family members; crystal structure of STBD1 LIR/GABARAPL1 complex defined the molecular basis of this interaction. STBD1 directly binds the Claw domain of RB1CC1 (FIP200) through its LIR motif, recruiting this key autophagy-initiation factor. Cell-based assays confirmed that both LIR/GABARAPL1 interaction and intact dual oligosaccharide-binding sites are required for effective glycophagy complex formation. X-ray crystallography (CBM20-maltotetraose and LIR/GABARAPL1 complex structures), mass spectrometry, biochemical binding assays, structural modeling, cell-based fluorescence assays with LIR/CBM20 mutants Proceedings of the National Academy of Sciences of the United States of America High 39236246
2020 During ER stress, STBD1 is markedly upregulated through the PERK signaling branch of the UPR pathway and is required for the formation of glycogen-containing ER structures (glycogen clustering). In the absence of ER stress, STBD1 overexpression alone is sufficient to induce glycogen clustering. Failure to induce glycogen clustering during ER stress (Stbd1 loss-of-function) was associated with enhanced apoptotic pathway activation, supporting a pro-survival role for STBD1-mediated glycogen clustering. shRNA knockdown, STBD1 overexpression, PERK pathway inhibition, immunofluorescence microscopy of glycogen structures, apoptosis assays in mouse myoblasts Journal of cell science Medium 32958708
2022 Stbd1-knockout mice displayed reduced hepatic glycogen content, insulin resistance (increased fasting glucose and insulin, attenuated insulin signaling in liver and skeletal muscle, elevated liver sphingomyelin), and enhanced ER-mitochondria association with increased mitochondrial fragmentation in the liver, linking STBD1's role at MAMs to glucose homeostasis control. Stbd1 targeted knockout mice, glucose/insulin tolerance tests, insulin signaling immunoblotting, electron microscopy of ER-mitochondria contacts, mitochondrial respiratory chain enzyme activity assays, lipidomics Biochimie Medium 35691532
2025 STBD1 targets lipid droplets (LDs) via N-terminal myristoylation and mediates glycogen-LD colocalization in clear cell renal cell carcinoma. STBD1 depletion decreases LD abundance and impairs both glycophagy and lipophagy, and alters lipid composition, establishing STBD1 as a mediator of crosstalk between glycogen and lipid droplet metabolism. Proximity labeling (BioID) of LD proteome, STBD1 knockdown in vitro and in vivo, lipid droplet quantification, glycophagy/lipophagy flux assays, lipidomics, myristoylation-deficient mutant targeting assay Cell reports Medium 41105508
2025 Stbd1 overexpression in hepatocytes enhances AMPK activation and improves insulin sensitivity/insulin resistance; this AMPK activation and improved insulin response occurred independently of N-myristoylation, ERMC number changes, glycogen levels, mitochondrial calcium, morphology, and respiratory function, placing STBD1 upstream of AMPK as an activator. Stbd1 overexpression (including myristoylation-deficient mutant) in hepatocyte cell model, AMPK phosphorylation immunoblotting, insulin signaling assays, mitochondrial function assays, calcium measurements The FEBS journal Medium 40001216

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: Identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochemical and biophysical research communications 139 21893048
2017 Mouse Stbd1 is N-myristoylated and affects ER-mitochondria association and mitochondrial morphology. Journal of cell science 25 28137759
2014 The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein-protein interactions. Bioscience reports 25 24837458
2013 Stbd1 is highly elevated in skeletal muscle of Pompe disease mice but suppression of its expression does not affect lysosomal glycogen accumulation. Molecular genetics and metabolism 25 23726947
2019 Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates. Cellular signalling 23 30772465
2024 Decoding the molecular mechanism of selective autophagy of glycogen mediated by autophagy receptor STBD1. Proceedings of the National Academy of Sciences of the United States of America 14 39236246
2020 Stbd1 promotes glycogen clustering during endoplasmic reticulum stress and supports survival of mouse myoblasts. Journal of cell science 14 32958708
2022 Stbd1-deficient mice display insulin resistance associated with enhanced hepatic ER-mitochondria contact. Biochimie 11 35691532
2023 Glycogen-binding protein STBD1: Molecule and role in pathophysiology. Journal of cellular physiology 9 37435888
2025 Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model. The FEBS journal 2 40001216
2026 Glycophagy is an ancient bilaterian pathway supporting metabolic adaptation through STBD1 structural evolution. Communications biology 1 41559265
2025 STBD1 mediates the crosstalk between glycogen and lipid droplets in clear cell renal cell carcinoma. Cell reports 1 41105508
2025 Asiatic Acid Alleviates Renal Damage by Upregulating STBD1-Mediated Glycophagy in Diabetic Kidney Disease. Biomedicines 0 40722620

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