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Showing SACM1L — SAC1 is a alias.

SACM1L

Phosphatidylinositol-3-phosphatase SAC1 · UniProt Q9NTJ5

Length
587 aa
Mass
67.0 kDa
Annotated
2026-06-10
66 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SACM1L (SAC1) is a conserved integral ER membrane phosphoinositide phosphatase that controls the spatial distribution of PI(4)P across the secretory pathway, coupling lipid homeostasis to membrane trafficking, organelle architecture, and cytoskeletal organization (PMID:10224048, PMID:10887188, PMID:18480408). Its SAC1-homology catalytic domain hydrolyzes PI(3)P, PI(4)P, and PI(3,5)P2 to PI but spares PI(4,5)P2, and PI(4)P phosphatase activity is the function essential for cellular viability and for complementing yeast Sac1 defects (PMID:10224048, PMID:10887188). The catalytic domain folds into an N-terminal subdomain packed against the PI-phosphatase subdomain with a distinctive P-loop and a large cationic catalytic groove, and the enzyme is allosterically activated by anionic phospholipid products binding this groove (PMID:20389282, PMID:22452743). SAC1 acts predominantly in cis at the ER, degrading PI(4)P locally to sustain a steep PI(4)P gradient between donor membranes and the ER (PMID:29461204); at ER–TGN contact sites it can additionally act in trans through the adaptor FAPP1 (PMID:30659099). SAC1 dynamically cycles between ER and Golgi: ER export uses a 14-3-3/Sec24-dependent LS sorting motif into COPII vesicles, while retrieval from the Golgi requires a C-terminal KXKXX motif that binds the COPI complex, and its first transmembrane domain and N-terminal cytoplasmic domain independently confer Golgi retention (PMID:14527956, PMID:26056309, PMID:23936490). This trafficking, and hence Golgi PI(4)P levels, is regulated by p38 MAPK-driven oligomer dissociation, by EGF/Ca2+/Duox-dependent H2O2 oxidation of the catalytic Cys389–Cys392 pair, and by the GOLPH3 ortholog Vps74, which binds the catalytic domain directly to target medial-Golgi PI(4)P (PMID:18299350, PMID:30476538, PMID:30448513, PMID:22553352, PMID:25113029). Through this control of organelle PI(4)P pools, SAC1 maintains Golgi V-ATPase assembly and TGN acidification, governs mitotic spindle organization, enables autophagosome–lysosome fusion and xenophagy of Salmonella, and directs developmental processes including Slit/Robo-dependent axon guidance and JNK-dependent epithelial morphogenesis (PMID:40841558, PMID:18480408, PMID:32693712, PMID:34320354, PMID:22042447, PMID:14588244). Loss of murine Sac1 causes preimplantation lethality, underscoring its essential role (PMID:18480408).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1989 High

    Before any enzymatic role was known, genetics placed Sac1 at a node coordinating secretion and the actin cytoskeleton, framing it as a shared regulator of these processes.

    Evidence Genetic suppressor screen and double-mutant epistasis in yeast against sec14/sec6/sec9 and actin mutants

    PMID:2687291

    Open questions at the time
    • No molecular activity assigned
    • Mechanistic link between secretion and actin unresolved
  2. 1999 High

    Established that the SAC1 domain is itself a phosphoinositide phosphatase with defined substrate range, converting genetic phenotypes into a concrete enzymatic activity.

    Evidence In vitro phosphatase assay on purified recombinant SAC1 domain plus lipid mass measurement in sac1 deletion yeast

    PMID:10224048

    Open questions at the time
    • Did not resolve which substrate is physiologically dominant
    • No structural basis for catalysis
  3. 1999 Medium

    Defined how PI(4)P accumulation in sac1 mutants is functionally read out, showing PLD-generated DAG rather than PI(4)P itself drives Sec14 bypass.

    Evidence Phospholipid metabolic labeling, PLD inactivation, and bacterial DAG kinase expression in yeast

    PMID:10397762

    Open questions at the time
    • Single-lab biochemical dissection
    • Relevance to mammalian Sac1 not tested
  4. 2000 High

    Showed the mammalian enzyme conserves substrate specificity and that PI(4)P phosphatase activity specifically is the function required in vivo, prioritizing PI(4)P as the key substrate.

    Evidence In vitro assay with active-site mutants and heterologous yeast complementation of rat Sac1

    PMID:10887188

    Open questions at the time
    • Did not address subcellular site of action
    • Roles of PI(3)P/PI(3,5)P2 activity left open
  5. 2001 High

    Localized Sac1 turnover activity to the ER and identified Stt4 as the kinase generating its PI(4)P substrate pool, establishing a kinase–phosphatase axis.

    Evidence Temperature-sensitive alleles, microscopy, and reciprocal epistasis with stt4 and pik1 in yeast

    PMID:11514624

    Open questions at the time
    • Did not explain ER/Golgi cycling
    • Mechanism connecting PI(4)P to vacuole/lipid-droplet phenotypes unresolved
  6. 2003 High

    Defined the molecular logic of ER retrieval, linking a C-terminal KXKXX COPI motif to catalytic state and showing enzymatic activity gates COPI engagement.

    Evidence Co-IP with COPI, KXKXX and catalytic-dead mutagenesis, and localization in mammalian cells

    PMID:14527956

    Open questions at the time
    • ER export pathway not yet defined
    • Structural basis of activity-dependent motif accessibility unknown
  7. 2003 Medium

    Extended Sac1 function into metazoan development, placing it upstream of or parallel to JNK signaling in epithelial morphogenesis.

    Evidence Drosophila sac1 loss-of-function with dosage-sensitive interactions with JNK pathway components

    PMID:14588244

    Open questions at the time
    • Lipid mechanism linking Sac1 to JNK not defined
    • Single organism
  8. 2007 Medium

    Resolved how Sac1 selects a kinase-specific PI(4)P pool, showing growth-dependent shuttling between Dpm1 at the ER and Pik1-generated Golgi PI(4)P via COPII/Rer1.

    Evidence Co-IP, COPII/Rer1 mutant analysis, and condition-dependent PI(4)P measurements in yeast

    PMID:17908202

    Open questions at the time
    • Single-lab Co-IP evidence
    • Mammalian conservation of Rer1 adaptor untested
  9. 2008 High

    Connected Sac1 localization to mitogenic signaling, establishing p38 MAPK-driven oligomer dissociation as a switch releasing the Golgi secretion brake.

    Evidence Fractionation, microscopy, kinase inhibition, and PI(4)P measurements in mammalian cells

    PMID:18299350

    Open questions at the time
    • Oligomerization interface not mapped
    • Direct p38 substrate site on SAC1 unidentified
  10. 2008 High

    Demonstrated organismal essentiality and assigned a mitotic role, showing both phosphatase activity and ER recycling are required in vivo.

    Evidence Sac1 knockout mouse, RNAi, and rescue with phosphatase-dead and ER-localization-defective mutants

    PMID:18480408

    Open questions at the time
    • Molecular basis of spindle defect unresolved
    • Lethality stage limits tissue-level analysis
  11. 2010 High

    Provided the structural framework, revealing a two-subdomain fold with a cationic catalytic groove implying an unusual dephosphorylation mechanism.

    Evidence 2.0 Å X-ray crystal structure of the yeast Sac phosphatase domain

    PMID:20389282

    Open questions at the time
    • Membrane-engaged conformation not captured
    • Substrate-bound state absent
  12. 2012 Medium

    Identified an allosteric activation mechanism by anionic phospholipids, linking product and membrane lipid composition to catalytic output.

    Evidence In vitro phosphatase assays with defined lipid species interpreted on the crystal structure

    PMID:22452743

    Open questions at the time
    • Conformational change inferred, not directly observed
    • Single-lab in vitro evidence
  13. 2012 High

    Defined GOLPH3/Vps74 as a direct PI(4)P-level sensor that recruits Sac1 to medial-Golgi cisternae, explaining sub-Golgi targeting.

    Evidence Quantitative in vitro binding (Kd 3.8 µM), PI(4)P reporter distribution, and genetic deletion in yeast

    PMID:22553352

    Open questions at the time
    • Mammalian GOLPH3-SAC1 functional equivalence not shown here
    • Regulation of the interaction unknown
  14. 2013 Medium

    Dissected the membrane determinants of Golgi retention, showing TM1 alone is sufficient and portable, with an additional N-terminal cytoplasmic contribution.

    Evidence Truncation and chimeric constructs with transferrin receptor 2 in mammalian cells

    PMID:23936490

    Open questions at the time
    • Retention partners of TM1 unidentified
    • Single-lab localization data
  15. 2014 High

    Visualized the Sac1–Vps74 interface and showed its disruption broadens Golgi PI(4)P and mislocalizes a Golgi enzyme, tying lipid targeting to glycosylation residency.

    Evidence Crystal structure of the Sac1–Vps74 complex with interface mutagenesis and PI(4)P/enzyme localization assays

    PMID:25113029

    Open questions at the time
    • In vivo dynamics of the complex not resolved
    • Conservation to human GOLPH3 structurally untested
  16. 2015 High

    Defined the ER export step, identifying a 14-3-3-dependent LS sorting motif and Sec24 engagement that package SAC1 into COPII vesicles.

    Evidence Cell-free COPII budding reconstitution, Sec24/14-3-3 Co-IP, and LS-motif mutagenesis

    PMID:26056309

    Open questions at the time
    • Phosphorylation controlling 14-3-3 binding not mapped
    • Coupling to p38 oligomer regulation unresolved
  17. 2018 High

    Resolved the long-standing cis-versus-trans question, showing SAC1 acts locally at the ER to maintain a steep PI(4)P gradient with little intrinsic trans activity.

    Evidence Acute chemical inhibition, live-cell PI(4)P biosensors, and engineered-linker trans-activity tests

    PMID:29461204

    Open questions at the time
    • Did not exclude adaptor-assisted trans activity
    • Identity of counter-transported lipids inferred not measured here
  18. 2018 High

    Established redox regulation, identifying EGF/Ca2+/Duox-driven H2O2 oxidation of catalytic Cys389–Cys392 as a transient brake on Golgi PI(4)P turnover.

    Evidence Mass spectrometry of oxidized cysteines, Golgi-targeted H2O2 probe, Duox knockdown, and PI(4)P measurements

    PMID:30448513 PMID:30476538

    Open questions at the time
    • Reductase reversing oxidation unidentified
    • Physiological output of transient oxidation not quantified
  19. 2019 High

    Reconciled cis activity with TGN PI(4)P control by identifying FAPP1 as an adaptor enabling SAC1 trans activity at ER–TGN contact sites.

    Evidence Reciprocal Co-IP, in vitro trans-phosphatase assay, and FAPP1 knockdown with PI(4)P/cargo readouts

    PMID:30659099

    Open questions at the time
    • Structural basis of FAPP1-mediated trans activation unknown
    • Cargo selectivity mechanism unresolved
  20. 2019 High

    Identified TMEM39A/SUSR2 as a transport regulator coupling SAC1 ER-export to autophagy, linking SAC1 retention to PI(3)P and endolysosomal PI(4)P.

    Evidence Reciprocal Co-IP with SAC1 and SEC23/SEC24, knockdown with lipid measurements, and autophagy/HOPS assays

    PMID:31806350

    Open questions at the time
    • Direct vs indirect effect on VPS34 not fully separated
    • Mechanism of SUSR2-COPII coordination undefined
  21. 2020 Medium

    Connected SAC1 to neuronal metabolic sensing, showing CPT1C tunes SAC1 activity to gate AMPA-receptor subunit trafficking under glucose stress.

    Evidence SAC1 activity assays under CPT1C modulation, glucose-depletion stress, PI(4)P measurements, and GluA1 surface trafficking

    PMID:32931550

    Open questions at the time
    • Direct biochemical mechanism of CPT1C inhibition unresolved
    • Single-lab evidence
  22. 2011 Medium

    Placed Sac1 catalytic activity in the Slit/Robo axon-repulsion pathway, requiring PI phosphatase activity for proper midline guidance.

    Evidence Drosophila sac1 mutants rescued by WT but not catalytic-dead Sac1, with slit/robo dosage interactions

    PMID:22042447

    Open questions at the time
    • Lipid intermediate linking Sac1 to Robo signaling not defined
    • Single organism
  23. 2018 Medium

    Linked Sac1 PI(4)P control to microtubule-dependent exocyst trafficking in a developmental epithelium.

    Evidence Conditional Drosophila sac1 allele with PI(4)P imaging, microtubule staining, and Roughest/Sec8 localization

    PMID:29752385

    Open questions at the time
    • Mechanism connecting PI(4)P to microtubule stability unresolved
    • Single-lab data
  24. 2020 High

    Defined SAC1's role in autophagosome maturation, showing PI(4)P clearance is required for SNARE-mediated autophagosome–lysosome fusion, conserved across species.

    Evidence Yeast screen plus PI(4)P imaging, SNARE recruitment, Atg9-vesicle lipid analysis, and mammalian validation

    PMID:32693712

    Open questions at the time
    • Direct SNARE-PI(4)P regulatory link not fully resolved
    • Site of relevant SAC1 action during fusion unclear
  25. 2021 High

    Extended the autophagy role to host defense, showing SAC1 clears PI(4)P from Salmonella-containing autophagosomes to block the PI(4)P-binding effector SteA.

    Evidence siRNA knockdown, PI(4)P imaging on pathogen autophagosomes, and epistasis with SteA-deletion Salmonella

    PMID:34320354

    Open questions at the time
    • How SAC1 accesses pathogen membranes undefined
    • Other PI(4)P-binding effectors not surveyed
  26. 2024 Medium

    Tested the limits of compartment-specific action by re-targeting SAC1 to PM–mitochondria contacts, implicating ORP2 as the lipid-transfer mediator delivering PM PI(4)P to SAC1.

    Evidence Organelle-targeted SAC1 chimeras with ORP2 knockdown and live-cell PM PI(4)P biosensors

    PMID:38327560

    Open questions at the time
    • Engineered system may not reflect endogenous geometry
    • Direct ORP2-SAC1 coupling not shown
  27. 2025 High

    Linked SAC1 TGN lipid control to organelle acidification, showing acute loss disassembles the V-ATPase via the V0a2 subunit conformation and impairs glycosylation.

    Evidence Auxin-inducible SAC1 degron with lipid biosensors, V-ATPase assembly and V0a2 conformation assays, and glycosylation readouts

    PMID:40841558

    Open questions at the time
    • Relative contributions of PI(4)P rise vs cholesterol drop not separated
    • How lipids set V0a2 conformation mechanistically undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (p38 oligomer dissociation, 14-3-3/COPII export, COPI retrieval, redox oxidation, GOLPH3/FAPP1/CPT1C adaptors) are integrated to set organelle-specific PI(4)P set points in real time remains unresolved.
  • No unified quantitative model of SAC1 cycling and activity
  • Hierarchy and crosstalk among regulators unmapped
  • Human structural basis for adaptor-controlled trans activity lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0008289 lipid binding 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2
Partners
14-3-3COPICPT1CDPM1FAPP1GOLPH3/VPS74SEC24TMEM39A/SUSR2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The SAC1-like domain of yeast Sac1p defines a novel class of polyphosphoinositide phosphatase (PPIPase) with intrinsic enzymatic activity. Purified recombinant SAC1-like domain converts PI 3-phosphate, PI 4-phosphate, and PI 3,5-bisphosphate to PI, whereas PI 4,5-bisphosphate is not a substrate. Yeast lacking Sac1p exhibit 10-, 2.5-, and 2-fold increases in PI 4-phosphate, PI 3,5-bisphosphate, and PI 3-phosphate respectively. Purified recombinant protein in vitro phosphatase assay; lipid mass measurement in sac1 deletion yeast strains The Journal of biological chemistry High 10224048
1989 Mutations in SAC1 suppress defects in both yeast Golgi secretion (sec14, sec6, sec9 mutants) and actin cytoskeleton function, placing Sac1p at a node that coordinates secretory pathway and actin cytoskeleton activities. Genetic suppressor screen; double-mutant epistasis analysis The Journal of cell biology High 2687291
2000 Rat (mammalian) Sac1 is a ubiquitously expressed 65-kDa integral membrane protein of the ER with intrinsic phosphoinositide phosphatase activity directed toward PI 3-phosphate, PI 4-phosphate, and PI 3,5-bisphosphate. Mutant rat sac1 alleles evoke substrate-specific defects in enzymatic activity. PI 4-phosphate phosphatase activity, but not PI 3-phosphate or PI 3,5-bisphosphate phosphatase activity, is essential for complementation of yeast Sac1p defects in vivo. In vitro phosphatase assay with purified recombinant protein; active-site mutagenesis; heterologous complementation in yeast deletion strains The Journal of biological chemistry High 10887188
2001 Sac1p localizes primarily to the ER, and this localization is crucial for efficient turnover of PI 4-phosphate. The bulk of PI 4-phosphate that accumulates in sac1 mutant cells is generated by the Stt4 PI 4-kinase (not Pik1p), as demonstrated by double-mutant analysis. Loss of Sac1p activity causes vacuole morphology changes, lipid droplet accumulation, and Golgi function defects. Temperature-sensitive allele analysis; fluorescence microscopy for localization; double-mutant epistasis with stt4(ts) and pik1(ts); lipid measurements Molecular biology of the cell High 11514624
2003 Human SAC1 (hSAC1) exhibits the same substrate specificity as yeast Sac1p, localizes to the ER and Golgi, and interacts physically with COPI complex subunits. Mutation of a C-terminal KXKXX motif abolishes COPI interaction and causes hSAC1 accumulation in the Golgi. A catalytically inactive mutant also accumulates in the Golgi and fails to interact with COPI despite an intact KXKXX motif, suggesting that enzymatic activity provides a switch for COPI interaction motif accessibility. Co-immunoprecipitation; KXKXX motif mutagenesis; catalytic-dead mutant; subcellular localization by immunofluorescence The Journal of biological chemistry High 14527956
2008 SAC1 accumulates at the Golgi in quiescent mammalian cells, depleting Golgi PI(4)P and down-regulating anterograde trafficking. Golgi localization requires SAC1 oligomerization and COPII recruitment. Mitogen stimulation activates the p38 MAPK pathway, which dissociates SAC1 oligomers, triggering COPI-mediated retrieval of SAC1 to the ER and releasing the brake on Golgi secretion. Subcellular fractionation; fluorescence microscopy; dominant-negative and kinase inhibitor experiments; p38 MAPK inhibition; PI(4)P measurements The Journal of cell biology High 18299350
2008 Functional ablation of murine Sac1 results in preimplantation lethality. Sac1 insufficiency causes disorganization of mammalian Golgi membranes and mitotic defects with multiple mechanically active spindles. Both phosphoinositide phosphatase activity and ER localization (recycling from Golgi to ER) are required for Sac1 function in vivo. Sac1 knockout mouse; RNAi knockdown in mammalian cells; complementation with phosphatase-dead and ER-localization-defective mutants; fluorescence microscopy Molecular biology of the cell High 18480408
2010 Crystal structure of the Sac phosphatase domain of yeast Sac1 at 2.0 Å resolution reveals two closely packed sub-domains: a novel N-terminal sub-domain and the PI phosphatase catalytic sub-domain. The structure shows a unique conformation of the catalytic P-loop and a large positively charged groove at the catalytic site, suggesting an unusual dephosphorylation mechanism. X-ray crystallography at 2.0 Å; homology modeling of human Fig4/Sac3 The EMBO journal High 20389282
2007 During exponential growth, Sac1p interacts with Dpm1p at the ER. During starvation, Sac1p shuttles to the Golgi via COPII and Rer1 adaptor protein, specifically eliminating a pool of PI(4)P generated by Pik1p/Frq1p. Reciprocal association/dissociation of Sac1p and the Pik1p/Frq1p kinase complex controls growth-dependent Golgi PI(4)P levels. Co-immunoprecipitation (Sac1p-Dpm1p interaction); COPII and Rer1 mutant analysis; PI(4)P measurements under different growth conditions; fluorescence microscopy Traffic (Copenhagen, Denmark) Medium 17908202
2012 Vps74 (yeast ortholog of human GOLPH3) binds directly to the catalytic domain of Sac1 (Kd = 3.8 μM) and functions as a sensor of PI(4)P levels on medial Golgi cisternae, directing Sac1-mediated dephosphorylation of this PI(4)P pool. In vitro binding assay (fluorescence anisotropy/ITC for Kd); PI(4)P reporter distribution analysis; genetic deletion epistasis Molecular biology of the cell High 22553352
2012 Sac1 is allosterically activated by anionic phospholipids: its product phosphatidylinositol and phosphatidylserine activate the enzyme, likely through conformational changes of the catalytic P-loop induced by binding of anionic phospholipids in the large cationic catalytic groove. In vitro phosphatase assay with purified recombinant Sac1; analysis of activation by different lipid species; structural interpretation based on crystal structure Biochemistry Medium 22452743
2014 Crystal structure of the N-terminal portion of yeast Sac1 in complex with Vps74 reveals the interaction interface involves the N-terminal subdomain of the Sac1 homology domain. Disruption of the Sac1-Vps74 interface results in broader distribution of PI(4)P within the Golgi and failure to maintain residence of a medial Golgi mannosyltransferase. X-ray crystallography of Sac1-Vps74 complex; interface mutagenesis; PI(4)P reporter imaging; Golgi resident enzyme localization assay The Journal of cell biology High 25113029
2015 14-3-3 protein acts as a cytosolic adaptor mediating SAC1 export from the ER in COPII-coated vesicles. Recombinant 14-3-3 stimulates packaging of SAC1 into COPII vesicles in a cell-free budding reaction. The COPII sorting subunit Sec24 interacts with 14-3-3. A minimal sorting motif (RLSNTSP, the 'LS motif') in SAC1 is required for 14-3-3 binding and controls SAC1 ER export. Cell-free COPII vesicle budding assay; Co-immunoprecipitation of Sec24 with 14-3-3; SAC1 motif mutagenesis; recombinant protein addition Proceedings of the National Academy of Sciences of the United States of America High 26056309
2018 SAC1 acts in 'cis' configuration at the ER to degrade PtdIns4P, maintaining a steep PtdIns4P chemical gradient with donor membranes. Acute chemical inhibition of SAC1 causes PtdIns4P accumulation in the ER. SAC1 does not enrich at membrane contact sites and has little activity in 'trans' unless an artificial linker is added between its ER-anchor and catalytic domains. Acute chemical inhibition of SAC1; live-cell PtdIns4P biosensors; SAC1 localization imaging; engineered linker constructs for trans-activity test eLife High 29461204
2018 SAC1 undergoes reversible oxidative inactivation in mammalian cells: H2O2 oxidizes the catalytic Cys389 residue to form an intramolecular disulfide with Cys392, causing accumulation of PtdIns(4)P at the Golgi. EGF stimulation induces Ca2+-dependent Duox activation, H2O2 production at the Golgi, and transient SAC1 oxidation, linking EGF signaling to Golgi PtdIns(4)P control. Mass spectrometry of oxidized cysteines; Golgi-confined SAC1-K2A mutant; Duox knockdown; Golgi-targeted H2O2 probe; PtdIns(4)P measurements Free radical biology & medicine High 30448513 30476538
2019 SAC1 activity on TGN PI(4)P occurs in-trans at ER-TGN contact sites (ERTGoCS) and requires the adaptor protein FAPP1. FAPP1 localizes at ERTGoCS, physically interacts with SAC1, and promotes SAC1's in-trans phosphatase activity in vitro. FAPP1 depletion increases TGN PI(4)P levels and enhances secretion of selected cargoes (e.g., ApoB100). Co-immunoprecipitation of FAPP1 with SAC1; in vitro trans-phosphatase activity assay; FAPP1 knockdown with PI(4)P and cargo secretion readouts; fluorescence localization The Journal of cell biology High 30659099
2019 TMEM39A/SUSR2 interacts with SAC1 and COPII SEC23/SEC24 subunits to promote ER-to-Golgi transport of SAC1. Depletion of SUSR2 retains SAC1 on the ER, increases PI(3)P produced by VPS34 complex, promotes autophagosome formation, and elevates late endosomal/lysosomal PI(4)P levels to facilitate HOPS complex recruitment and autophagosome maturation. Co-immunoprecipitation of SUSR2 with SAC1 and SEC23/SEC24; SUSR2 knockdown with PI(4)P and PI(3)P measurements; autophagy flux assays; HOPS recruitment assays Molecular cell High 31806350
2020 CPT1C (a malonyl-CoA sensor in the ER of neurons) regulates SAC1 catalytic activity: in normal conditions CPT1C down-regulates SAC1 activity, allowing efficient GluA1 (AMPA receptor subunit) trafficking to the plasma membrane. Under low malonyl-CoA (glucose depletion), CPT1C-dependent inhibition of SAC1 is released, SAC1 translocates to ER-TGN contact sites, decreasing TGN PI(4)P and triggering GluA1 retention at the TGN. SAC1 activity assay under CPT1C modulation; metabolic stress experiments (glucose depletion); PI(4)P measurements; GluA1 surface trafficking assay; SAC1 localization by fluorescence microscopy The Journal of cell biology Medium 32931550
2013 The first transmembrane domain (TM1) of human SAC1 is sufficient for Golgi localization. A minimal TM1-containing construct concentrates at the Golgi, and transplanting TM1 into transferrin receptor 2 induces Golgi accumulation of that normally PM/endosomal protein. The N-terminal cytoplasmic domain of SAC1 also independently promotes Golgi localization. Truncation and chimeric constructs expressed in mammalian cells; fluorescence microscopy localization PloS one Medium 23936490
2003 Drosophila Sac1 loss-of-function causes defects in dorsal closure: specifically, improper activation of cell shape change in the amnioserosa and JNK signaling in the leading edge epidermis. sac1 shows dosage-sensitive genetic interactions with components of the JNK cascade and cell shape change pathway, placing Sac1 upstream or parallel to these events. Drosophila sac1 loss-of-function mutant analysis; genetic interaction (dosage-sensitive) with JNK pathway components; embryo phenotype imaging Current biology : CB Medium 14588244
2011 Drosophila Sac1 is required for axon guidance at the CNS midline. sac1 mutants show ectopic midline crossing of Fasciclin II-positive axon tracts. This phenotype is rescued by neuronal expression of wild-type Sac1 but not by a catalytically-inactive mutant. sac1 shows dosage-sensitive genetic interactions with slit and robo, placing Sac1-mediated PI regulation in the Slit/Robo axon repulsion pathway. Drosophila sac1 loss-of-function mutants; neuronal rescue with WT vs. catalytic-dead Sac1; dosage-sensitive genetic interaction with slit and robo Molecules and cells Medium 22042447
2021 SAC1 is required for autophagosome-lysosome fusion through its PI(4)P phosphatase activity. Sac1 deficiency causes dramatic accumulation of PI(4)P at early Golgi and abnormal incorporation of PI(4)P into Atg9 vesicles and autophagosomes, leading to failure to recruit SNARE proteins for autophagosome fusion with vacuoles. This function is conserved from yeast to mammalian cells. High-throughput screen in S. cerevisiae followed by mechanistic validation; PI(4)P reporter imaging; SNARE recruitment assays; Atg9 vesicle lipid analysis; mammalian cell validation Autophagy High 32693712
2021 SAC1 (SACM1L) is an essential regulator of xenophagy: depletion or inactivation of SAC1 results in aberrant accumulation of PI(4)P on Salmonella-containing autophagosomes, facilitating recruitment of the PI(4)P-binding Salmonella effector SteA, which impedes lysosomal fusion. Replication of Salmonella lacking SteA is suppressed by SAC1-deficient cells, confirming the mechanism. siRNA knockdown of SAC1; PI(4)P imaging on pathogen-containing autophagosomes; bacterial replication assays with SteA deletion Salmonella; epistasis between SAC1 and SteA Cell reports High 34320354
2025 Acute Sac1 degradation (auxin-inducible degron) in human cells causes immediate PI(4)P increase and cholesterol decrease in the TGN, followed by Golgi V-ATPase disassembly, TGN deacidification, Golgi fragmentation, and impaired glycosylation. Mechanistically, Sac1-mediated TGN membrane lipid composition maintains an assembly-promoting conformation of the V0a2 subunit of the V-ATPase. Auxin-inducible degron system for acute Sac1 degradation; PI(4)P and cholesterol biosensors; V-ATPase assembly assay; V0a2 conformation analysis; glycosylation assays; differentiated trophoblast model Nature communications High 40841558
2024 Orthogonal targeting of SAC1 to mitochondria (PM-mitochondria contact sites) enhances PM PI(4)P turnover independently of ER-PM contact sites. This turnover is slowed by knockdown of soluble ORP2, implicating ORP2 as a major mediator of PI(4)P transfer from PM to sites where SAC1 can degrade it. Organelle-targeted SAC1 chimeras; ORP2 knockdown; live-cell PI(4)P biosensors at PM Contact (Thousand Oaks) Medium 38327560
1999 sac1 mutants exhibit accumulation of PI 4-phosphate that alone is insufficient to effect bypass of Sec14p function. Instead, phospholipase D activity generates diacylglycerol (DAG) downstream of elevated PI 4-phosphate, and this DAG effects bypass Sec14p. CDP-choline pathway activity contributes to the inositol auxotrophy of sac1 strains independently of INO1 transcription. Phospholipid metabolic labeling; genetic inactivation of phospholipase D; bacterial DAG kinase expression; sac1 mutant phenotype analysis Molecular biology of the cell Medium 10397762
2018 In Drosophila, Sac1 is required for normal photoreceptor cell shape and microtubule stability in the developing eye. Sac1 mutant interommatidial cells show elevated PI(4)P, severe microtubule organization defects, and accumulation of the adhesion protein Roughest and exocyst subunit Sec8 in enlarged intracellular vesicles. Roughest is delivered to the cell surface in Sac1 mutants, indicating that Sac1 acts in microtubule-dependent exocyst trafficking rather than Roughest surface delivery per se. Temperature-sensitive sac1 allele in Drosophila; PI(4)P imaging; microtubule immunostaining; Roughest and Sec8 localization; cold fixation ex vivo assay Development (Cambridge, England) Medium 29752385

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 SAC1-like domains of yeast SAC1, INP52, and INP53 and of human synaptojanin encode polyphosphoinositide phosphatases. The Journal of biological chemistry 333 10224048
2013 The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Human mutation 274 23804563
1989 Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function. The Journal of cell biology 212 2687291
2001 Sac1 lipid phosphatase and Stt4 phosphatidylinositol 4-kinase regulate a pool of phosphatidylinositol 4-phosphate that functions in the control of the actin cytoskeleton and vacuole morphology. Molecular biology of the cell 195 11514624
2017 The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals. The EMBO journal 185 28331029
2008 Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1. The Journal of cell biology 135 18299350
1999 Pleiotropic alterations in lipid metabolism in yeast sac1 mutants: relationship to "bypass Sec14p" and inositol auxotrophy. Molecular biology of the cell 125 10397762
2018 SAC1 degrades its lipid substrate PtdIns4P in the endoplasmic reticulum to maintain a steep chemical gradient with donor membranes. eLife 120 29461204
1996 Sac1, a putative regulator that is critical for survival of Chlamydomonas reinhardtii during sulfur deprivation. The EMBO journal 111 8641280
2000 Functional characterization of a mammalian Sac1 and mutants exhibiting substrate-specific defects in phosphoinositide phosphatase activity. The Journal of biological chemistry 104 10887188
2000 SAC1 encodes a regulated lipid phosphoinositide phosphatase, defects in which can be suppressed by the homologous Inp52p and Inp53p phosphatases. The Journal of biological chemistry 97 10625610
2010 Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function. The EMBO journal 89 20389282
2003 The human phosphatidylinositol phosphatase SAC1 interacts with the coatomer I complex. The Journal of biological chemistry 81 14527956
2006 Deletion of the adenylate cyclase (sac1) gene affects multiple developmental pathways and pathogenicity in Sclerotinia sclerotiorum. Fungal genetics and biology : FG & B 80 17178247
2008 The Sac1 phosphoinositide phosphatase regulates Golgi membrane morphology and mitotic spindle organization in mammals. Molecular biology of the cell 79 18480408
2007 Growth control of Golgi phosphoinositides by reciprocal localization of sac1 lipid phosphatase and pik1 4-kinase. Traffic (Copenhagen, Denmark) 73 17908202
2019 The activity of Sac1 across ER-TGN contact sites requires the four-phosphate-adaptor-protein-1. The Journal of cell biology 70 30659099
2018 Sac1, a lipid phosphatase at the interface of vesicular and nonvesicular transport. Traffic (Copenhagen, Denmark) 61 29411923
2005 Regulation of intracellular phosphatidylinositol-4-phosphate by the Sac1 lipid phosphatase. Traffic (Copenhagen, Denmark) 54 15634212
2012 Local control of phosphatidylinositol 4-phosphate signaling in the Golgi apparatus by Vps74 and Sac1 phosphoinositide phosphatase. Molecular biology of the cell 53 22553352
2018 Model of OSBP-Mediated Cholesterol Supply to Aichi Virus RNA Replication Sites Involving Protein-Protein Interactions among Viral Proteins, ACBD3, OSBP, VAP-A/B, and SAC1. Journal of virology 51 29367253
1981 Genetics of serum resistance in Neisseria gonorrhoeae: the sac-1 genetic locus. Infection and immunity 48 6788697
2019 The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1. Molecular cell 39 31806350
2015 Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America 36 26056309
2014 Sac1-Vps74 structure reveals a mechanism to terminate phosphoinositide signaling in the Golgi apparatus. The Journal of cell biology 34 25113029
2003 The Sac1 lipid phosphatase regulates cell shape change and the JNK cascade during dorsal closure in Drosophila. Current biology : CB 34 14588244
2012 Allosteric activation of the phosphoinositide phosphatase Sac1 by anionic phospholipids. Biochemistry 33 22452743
2020 Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking. The Journal of cell biology 30 32931550
2020 Co-opted Cellular Sac1 Lipid Phosphatase and PI(4)P Phosphoinositide Are Key Host Factors during the Biogenesis of the Tombusvirus Replication Compartment. Journal of virology 28 32269127
2008 SAC1 lipid phosphatase and growth control of the secretory pathway. Molecular bioSystems 27 19081929
2020 PtdIns4P restriction by hydrolase SAC1 decides specific fusion of autophagosomes with lysosomes. Autophagy 26 32693712
2017 A strategic approach for direct recovery and stabilization of Fusarium sp. ICT SAC1 cutinase from solid state fermented broth by carrier free cross-linked enzyme aggregates. International journal of biological macromolecules 22 28192137
1999 Mutations in the Saccharomyces cerevisiae gene SAC1 cause multiple drug sensitivity. Yeast (Chichester, England) 21 10455234
2017 Non-covalent conjugation of cutinase from Fusarium sp. ICT SAC1 with pectin for enhanced stability: Process minutiae, kinetics, thermodynamics and structural study. International journal of biological macromolecules 20 28442331
2014 Involvement of Sac1 phosphoinositide phosphatase in the metabolism of phosphatidylserine in the yeast Saccharomyces cerevisiae. Yeast (Chichester, England) 20 24578286
2015 The actin-related protein Sac1 is required for morphogenesis and cell wall integrity in Candida albicans. Fungal genetics and biology : FG & B 17 25575432
2021 SAC1 regulates autophagosomal phosphatidylinositol-4-phosphate for xenophagy-directed bacterial clearance. Cell reports 15 34320354
2001 Mammalian inositol polyphosphate 5-phosphatase II can compensate for the absence of all three yeast Sac1-like-domain-containing 5-phosphatases. The Biochemical journal 14 11311145
2023 Lipid phosphatase SAC1 suppresses hepatitis B virus replication through promoting autophagic degradation of virions. Antiviral research 12 37068596
2021 The SAC1 phosphatase domain of synaptojanin-1 is activated by interacting with polyunsaturated fatty acid-containing phosphatidic acids. FEBS letters 12 34387861
1994 The complete sequencing of a 24.6 kb segment of yeast chromosome XI identified the known loci URA1, SAC1 and TRP3, and revealed 6 new open reading frames including homologues to the threonine dehydratases, membrane transporters, hydantoinases and the phospholipase A2-activating protein. Yeast (Chichester, England) 12 7941750
2021 Osh6 Revisited: Control of PS Transport by the Concerted Actions of PI4P and Sac1 Phosphatase. Frontiers in molecular biosciences 11 34712698
2017 Characterization of a putative Plasmodium falciparum SAC1 phosphoinositide-phosphatase homologue potentially required for survival during the asexual erythrocytic stages. Scientific reports 11 28983103
2013 The first transmembrane domain of lipid phosphatase SAC1 promotes Golgi localization. PloS one 11 23936490
2024 Orthogonal Targeting of SAC1 to Mitochondria Implicates ORP2 as a Major Player in PM PI4P Turnover. Contact (Thousand Oaks (Ventura County, Calif.)) 10 38327560
2023 Mutation of DEFECTIVE EMBRYO SAC1 results in a low seed-setting rate in rice by regulating embryo sac development. Journal of experimental botany 10 36651501
2018 Inactivation of the PtdIns(4)P phosphatase Sac1 at the Golgi by H2O2 produced via Ca2+-dependent Duox in EGF-stimulated cells. Free radical biology & medicine 10 30476538
2017 Oxysterol-binding protein recruitment and activity at the endoplasmic reticulum-Golgi interface are independent of Sac1. Traffic (Copenhagen, Denmark) 10 28471037
2024 Sac1 links phosphoinositide turnover to cryptococcal virulence. mBio 7 38953635
2022 Sac1 phosphatidylinositol 4-phosphate phosphatase is a novel host cell factor regulating hepatitis B virus particles assembly and release. The FEBS journal 7 35816160
2021 Long Terminal Repeat Retrotransposon Afut4 Promotes Azole Resistance of Aspergillus fumigatus by Enhancing the Expression of sac1 Gene. Antimicrobial agents and chemotherapy 7 34516252
2011 The phosphoinositide phosphatase Sac1 is required for midline axon guidance. Molecules and cells 7 22042447
2010 Persistent detection of a novel MLL-SACM1L rearrangement in the absence of leukemia. Leukemia research 7 20553989
2019 Sac1 Phosphoinositide Phosphatase Regulates Foam Cell Formation by Modulating SR-A Expression in Macrophages. Biological & pharmaceutical bulletin 5 31155588
2018 The phosphoinositide phosphatase Sac1 regulates cell shape and microtubule stability in the developing Drosophila eye. Development (Cambridge, England) 5 29752385
2024 Orthogonal targeting of SAC1 to mitochondria implicates ORP2 as a major player in PM PI4P turnover. bioRxiv : the preprint server for biology 4 37693626
2018 Accumulation of PtdIns(4)P at the Golgi mediated by reversible oxidation of the PtdIns(4)P phosphatase Sac1 by H2O2. Free radical biology & medicine 4 30448513
2024 Asymmetric tethering by exocyst in vitro requires a Rab GTPase, an R-SNARE and a Sac1-sensitive phosphoinositide lipid. Molecular biology of the cell 3 38198574
2025 Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol. Nature communications 2 40841558
2015 Neither insufficiency nor overexpression of sac1 affects the accumulation of Aβ42 in Drosophila expressing Ab42. European review for medical and pharmacological sciences 2 26004612
2025 Maintenance of proper phosphatidylinositol-4-phosphate level by Stt4 and Sac1 contributes to vesicular transport to and from the plasma membrane. The Journal of biological chemistry 1 40550329
2024 Sac1 links phosphoinositide turnover to cryptococcal virulence. bioRxiv : the preprint server for biology 1 38293062
2020 Novel role of the phosphatidylinositol phosphatase Sac1 in membrane homeostasis and polarized growth in Candida albicans. International journal of medical microbiology : IJMM 1 32245626
2025 ZNF191 inhibits intrahepatic cholangiocarcinoma cell motility and metastasis through SAC1-mediated Cdc42 inactivation. International journal of biological macromolecules 0 40962084
2024 Effect of ATG8 or SAC1 deficiency on the cell proliferation and lifespan of the long-lived PMT1 deficiency yeast cells. FEMS microbiology letters 0 38258560
2020 Cellular homeostasis in the Drosophila retina requires the lipid phosphatase Sac1. Molecular biology of the cell 0 32186963

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