| 2016 |
SEZ6L is a physiological substrate of BACE1 in neurons. BACE1 cleaves SEZ6L near the membrane, releasing a soluble ectodomain (sSEZ6L). BACE1 inhibition increases neuronal surface levels of SEZ6L (shown by cell surface biotinylation) and reduces sSEZ6L in CSF of BACE1-deficient mice. Mass spectrometry mapped the BACE1 cleavage site in SEZ6L to a position close to the transmembrane domain. |
Primary neuron cultures with BACE1 inhibitor treatment, cell surface biotinylation, mass spectrometry cleavage-site mapping, CSF proteomics from BACE1-knockout mice, custom antibody validation |
Molecular neurodegeneration |
High |
27716410
|
| 2013 |
SEZ6L is a substrate of BACE1 (and not BACE2) in pancreatic β-cells, with BACE1 mediating ectodomain shedding of SEZ6L; BACE2 has non-redundant roles shedding a distinct substrate set (SEZ6L2, not SEZ6L). |
Quantitative proteomics of BACE1/BACE2 loss- and gain-of-function models in β-cells (in vitro and in vivo), systematic sheddome/secretome analysis |
The Journal of biological chemistry |
High |
23430253
|
| 2018 |
BACE1 controls the surface expression and proteolysis of SEZ6L in neurons; pharmacological BACE1 inhibition increases SEZ6L abundance at the neuronal cell surface (up to 7-fold by SUSPECS click-chemistry glycoprotein labeling), consistent with BACE1-mediated shedding controlling surface levels. |
SUSPECS (click chemistry-based surface glycoprotein biotinylation), label-free quantitative mass spectrometry, immunoblot validation in neurons and mouse brain |
Molecular & cellular proteomics |
High |
29716987
|
| 2000 |
SEZ6L encodes a 1024 amino acid transmembrane protein with multiple protein-protein interaction and signal transduction domains (determined by full-length cDNA sequencing combined with GENSCAN genomic prediction and RT-PCR). A 428 kb homozygous deletion at 22q12.1 encompassing SEZ6L was identified in a small cell lung cancer cell line, and missense mutations were detected in lung cancer cell lines. |
RT-PCR, GENSCAN gene prediction from genomic sequence, deletion breakpoint cloning, mutation screening of cancer cell lines |
Oncogene |
Medium |
11175339
|
| 2021 |
Sez6 family members (Sez6, Sez6L, Sez6L2) inhibit complement by two mechanisms: (1) accelerating dissociation of C3 convertases, and (2) acting as cofactors for Factor I to facilitate cleavage of C3b (but not C4b). For the classical pathway, Sez6L is a weak inhibitor compared to Sez6 (strong) and Sez6L2 (moderate). For the alternative pathway, all three family members inhibit at or above the level of the known complement regulator MCP. The CUB and complement control protein (CCP) domains in these proteins provide the structural basis for complement regulatory activity. |
In vitro complement inhibition assays (classical and alternative pathway C3b/iC3b opsonization), C3 convertase decay assay, Factor I cofactor assay with C3b and C4b substrates |
Frontiers in immunology |
High |
33936031
|
| 2021 |
SEZ6L constitutive knockout mice display motor phenotypes in adulthood (altered gait, decreased motor coordination) and increased anxiety-like behaviour, while spatial learning and memory are normal. Gross anatomy and proteome of the adult SEZ6L knockout cerebellum showed no major differences from wild type, suggesting contributions from non-cerebellar regions. |
SEZ6L constitutive knockout mouse behavioral testing (gait analysis, rotarod, Morris water maze, anxiety assays), cerebellar proteomics |
Molecular neurobiology |
Medium |
34958451
|
| 2020 |
Sez6 family triple knockout (lacking Sez6, Sez6L, and Sez6L2) mice show reduced dendritic spine density in the hippocampus and a shift to more immature spine morphologies in somatosensory cortex, along with impaired motor learning, motor coordination decline, impaired working and spatial short-term memory, enhanced stress responsiveness, and reversal learning deficit. This establishes the Sez6 family (including Sez6L) as regulators of dendritic spine structure and cognitive/motor function. |
Triple knockout mouse model, dendritic spine morphology analysis, behavioral battery (rotarod, Morris water maze, working memory, anxiety tests) |
Cerebral cortex |
Medium |
31711114
|
| 2018 |
In Niemann-Pick type C (NPC1-null) mouse brains, BACE1-mediated cleavage of Sez6L is enhanced, particularly in cortex, hippocampus, and cerebellum at terminal disease stage. Sez6L and BACE1 co-localize in increased puncta within the endolysosomal pathway in NPC1-null primary neurons, suggesting that a trafficking defect in the endolysosomal pathway drives enhanced BACE1 proteolysis of Sez6L. Sez6L is expressed in Purkinje neurons and its immunostaining is lost upon Purkinje cell neurodegeneration. |
Immunoblot quantification of Sez6L and sSez6L in regional brain lysates, immunofluorescence co-localization of Sez6L and BACE1 in primary cortical neurons and brain sections, comparison of NPC1-null vs. wild-type mice at two ages |
PloS one |
Medium |
29979789
|
| 2022 |
In 5xFAD Alzheimer's disease mouse brains, accumulation of BACE1 in peri-plaque regions and enhanced BACE1 levels do NOT increase proteolysis of Sez6L (or Sez6) compared to WT; instead, Sez6 and Sez6L show altered subcellular distribution in the area of amyloid plaques distinct from APP, BACE1, and LAMP1 localization. |
Immunoblot for Sez6L cleavage products in 5xFAD vs. WT mouse brains, immunofluorescence co-localization analysis in brain sections |
Mechanisms of ageing and development |
Medium |
35998821
|
| 2026 |
Sez6l is upregulated in dorsal root ganglion (DRG) in the spared nerve injury (SNI) neuropathic pain model. siRNA-mediated knockdown of Sez6l in SNI mice reduced inflammatory cytokines (IL-6, TNF-α, IL-1β) and alleviated mechanical allodynia and thermal hyperalgesia. ChIP experiments indicated that Foxo1 transcriptionally activates Sez6l. Mechanistically, Sez6l promotes neuropathic pain by activating the Wnt5a/Ca2+ signaling pathway in DRGs. |
SNI mouse model, siRNA knockdown, behavioral pain testing (von Frey, thermal hyperalgesia), ELISA for cytokines, ChIP for Foxo1 binding to Sez6l promoter, bioinformatics pathway analysis |
Frontiers in genetics |
Medium |
42083568
|
| 2013 |
RNAi knockdown of SEZ6L in cells affects LDL internalization and/or cellular free cholesterol levels. Overexpression of SEZ6L as a GFP-tagged fusion protein inversely modifies cellular cholesterol levels, and knockdown correlates with altered LDL-receptor levels, indicating SEZ6L has a cholesterol-regulatory function in cells. |
RNAi knockdown, LDL internalization assay, free cholesterol measurement, GFP-fusion overexpression, LDL-receptor level measurement |
PLoS genetics |
Low |
23468663
|