| Annotated protein: | Phosphatidylinositol-3-phosphatase SAC1 (EC 3.1.3.64) (Phosphatidylinositol-4-phosphate phosphatase) (Suppressor of actin mutations 1-like protein). Gene symbol: SACM1L. Taxonomy: Rattus norvegicus (Rat). Uniprot ID: Q9ES21 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ SACM1L |
| Ontology domain: | Biological Process |
| SynGO term: | neurotransmitter receptor transport to postsynaptic membrane (GO:0098969) |
| Synapse type(s): | hippocampus, glutamatergic |
| Annotated paper: | Yang G, et al. "JNK3 couples the neuronal stress response to inhibition of secretory trafficking" Sci Signal. 2013 Jul 9;6(283):ra57 PMID:23838184 |
| Figure(s): | Figures 3, 4, 5; Supplementary Figures 8, 10, 12, 13 |
| Annotation description: | Sac1 is a lipid phosphatase that shuttles between the ER and the Golgi complex where it metabolizes PI4P to phosphatidylinositol (PI) Supplementary Fig. S8: "Golgi-localized Sac1 metabolizes PI4P in neurons." Expressing FLAG-wild-type(wt)-Sac1 in rat hippocampal neurons reduced the abundance of PI4P (detected by labeling with Fapp1-GFP). Expression of Sac1-K2a, a mutant which accumulates in the Golgi, had less PI4P. Expression of Sac1-LZ (leucine zipper), which is shuttles less efficiently to the Golgi, had no effect on PI4P abundance. Expression of wt-Sac1, Sac1-K2a, or Sac1-LZ significantly reduced surface density of GluA1(Fig. S8B). These data "suggest that shuttling or sequestration of Sac1 at the Golgi inhibits secretory trafficking in neurons by metabolizing and thus depleting PI4P at the Golgi." Fig. 3: "JNK3 interacts with Sac1 to deplete PI4P in the Golgi complex." Endogenous JNK3 immunoprecipitated Sac1 in cortical neurons. The JNK3-Sac1 interaction was increased by treatment with NMDA, which induced the palmitoylation of JNK3 (Fig. 1E). Fig. S10: In vitro affinity binding assays showed purified JNK3 was able to bind Sac1 "suggesting a direct physical interaction between JNK3 and Sac1." Fig. 4. "JNK3 collaborates with Sac1 to mediate stress-induced repression of secretory trafficking and disruption of synaptic integrity." shRNA knockdown of Sac1 in hippocampal neurons significantly increased the abundance of PI4P (Fig. S12C). Knockdown of Sac1 attenuated the affects of JNK KD-Parlm, JNK3 KD and NMDA on surface GluA1 levels. "This suggests that Sac1, through its function in metabolizing PI4P, is a critical partner in the JNK3-mediated inhibition of secretory trafficking in response to neuronal stress." "Synthetic peptide blockade of the JNK3-Sac1 interaction protects neurons from GluR1 depletion in response to NMDA-induced stress." Incubation with both pep139 and pep412 was required to disrupt the JNK3-Sac1 interaction in rat hippocampal neurons (Fig. S13B). Blocking the JNK3-Sac1 interaction protected surface GluA1 density during NMDA treatment. Addition of pep139 and pep412 significantly attenuated the reduction of surface GluA1 in NMDA-treated hippocampal neurons, with no effect on basal surface GluA1 levels (Fig. 4C). The number of synaptic puncta in neurons treated with NMDA and the peptides was elevated compared to NMDA treatment alone (Fig. 4D). Fig. 5: Model for Sac1-JNK3 interaction in the Golgi. The interaction between Sac1 and JNK3 traps Sac1 in the Golgi, accelerating the metabolism of PI4P to PI. Normal secretion requires the enrichment of PI4P in the Golgi, therefore the Sac1-JNK3 interaction suppresses secretory trafficking and reducing surface AMPARs. Fig. 2A: In wt neurons, expression of kinase-deficient palmitoylated JNK3 (JNK3 KD-Parlm) prevented secretion of GluA1 from the Golgi and decreased the density of surface GluA1 puncta. |
| Evidence tracking, Biological System: | Cultured neurons Non-neuronal tissue |
| Evidence tracking, Protein Targeting: | RNAi / shRNA Over-expression Antagonist / agonist Antibody (detection) |
| Evidence tracking, Experiment Assay: | Confocal Western blot Protein-protein interaction (generic) |
| Annotator(s): | Hana Goldschmidt (ORCID:0000-0002-5676-366X) Richard Huganir (ORCID:0000-0001-9783-5183) |
| Lab: | Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205, USA |
| Additional literature: | Sac1-K2a mutant accumulates in the Golgi; Sac1-LZ (leucine zipper) mutant, is less efficient at shuttling to the Golgi @ PMID:18299350 |
| SynGO annotation ID: | 2574 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |