SDF4

SDF4/Cab45 is a soluble, lumenal calcium-binding protein resident in the trans-Golgi network that acts as a Ca2+-dependent sorting receptor for soluble secretory cargo (PMID:8609160, PMID:23266954). It was the first soluble protein shown to reside in the Golgi lumen, harboring six EF-hand motifs and an N-terminal signal sequence but no membrane anchor (PMID:8609160). Cab45 functions downstream of the secretory pathway Ca2+ ATPase SPCA1, which imports Ca2+ into the TGN lumen; upon Ca2+ binding, Cab45 reversibly assembles into oligomers that capture specific cargo proteins such as COMP and lysozyme C, and mutation of its Ca2+-binding sites abolishes both oligomerization and cargo sorting (PMID:23266954, PMID:27138253). Cab45 colocalizes with SPCA1 and its clients in discrete TGN microdomains, where it directs cargo into TGN-derived secretory vesicles (PMID:27138253). This activity is tuned by phosphorylation by the Golgi kinase Fam20C, which promotes Cab45 translocation into budding vesicles and enhances client export (PMID:32422653). Beyond conventional secretion, Cab45 governs the correct targeting of lysosomal hydrolase precursors, as its loss causes hypersecretion of unprocessed prosaposin and progranulin and aberrant perinuclear lysosome positioning (PMID:36398980), and it drives polarized apical secretion of soluble cargo in epithelial cells (PMID:37163315). A cytosolic splice variant, Cab45b, binds Munc18b, syntaxin 2, and syntaxin 3 in a Ca2+-dependent manner and is required for regulated zymogen exocytosis in pancreatic acini (PMID:17442889).

1. 1996 High

   Established that a soluble protein could permanently reside in the Golgi lumen, defining Cab45 as an EF-hand Ca2+-binding protein without a membrane anchor and raising the question of its functional role.

   Evidence Subcellular fractionation, immunofluorescence, Ca2+-binding assays and sequence analysis

   PMID:8609160

   Open questions at the time

   • No function assigned at this stage
   • Mechanism of lumenal retention without a membrane anchor unresolved
2. 2007 High

   Identified a cytosolic splice variant (Cab45b) operating in regulated exocytosis, showing the locus encodes functionally distinct isoforms beyond the Golgi-lumenal form.

   Evidence Yeast two-hybrid, in vitro and Ca2+ binding assays, reciprocal Co-IP, and antibody inhibition of amylase secretion in permeabilized pancreatic acini

   PMID:17442889

   Open questions at the time

   • Does not address how the cytosolic isoform is generated and targeted
   • Structural basis of Ca2+-dependent Munc18b binding unknown
3. 2012 High

   Defined Cab45's core function as a TGN cargo sorter operating downstream of SPCA1-mediated Ca2+ import, linking lumenal Ca2+ to cargo selection.

   Evidence RNAi knockdown, Ca2+ imaging, Co-IP of Cab45 with secretory cargo, secretion assays

   PMID:23266954

   Open questions at the time

   • Molecular mechanism of cargo capture not yet reconstituted
   • Cargo specificity determinants undefined
4. 2016 High

   Provided the biochemical mechanism: Ca2+ triggers reversible Cab45 oligomerization that drives specific cargo binding in TGN microdomains, validated by Ca2+-site mutagenesis.

   Evidence In vitro oligomerization and Ca2+-dependent cargo-binding assays, Ca2+-binding site mutagenesis, STED superresolution microscopy, cellular secretion assays

   PMID:27138253

   Open questions at the time

   • Structure of the oligomer-cargo complex unresolved
   • How distinct clients are discriminated remains unclear
5. 2020 High

   Showed Cab45 activity is post-translationally regulated, with Fam20C phosphorylation tuning oligomerization, TGN retention, and vesicle export.

   Evidence MS phosphosite identification, phosphomimetic mutagenesis, vesicle budding/secretion and oligomerization assays

   PMID:32422653

   Open questions at the time

   • Signals controlling Fam20C phosphorylation of Cab45 unknown
   • Whether phosphorylation alters cargo selectivity not addressed
6. 2023 Medium

   Extended Cab45's role to lysosomal hydrolase targeting and organelle positioning, identifying new clients (prosaposin, progranulin) beyond conventional secretory cargo.

   Evidence hiSPECs secretome analysis of Cab45-deficient cells, lysosomal marker immunofluorescence, processing Western blots

   PMID:36398980

   Open questions at the time

   • Direct binding of Cab45 to PSAP/PGRN not demonstrated
   • Link between hydrolase mistargeting and lysosome mispositioning mechanistically unresolved
7. 2023 Medium

   Demonstrated that the SPCA1–Cab45 axis directs polarized apical secretion, showing the sorting machinery operates in a directional context in epithelia.

   Evidence Cab45 siRNA, dominant-negative SPCA1, apical vs basolateral secretion assays in polarized MDCK cells

   PMID:37163315

   Open questions at the time

   • How Cab45 sorting is coupled to apical polarity machinery unknown
   • Single epithelial cell model
8. 2021 Medium

   Reported a non-canonical extracellular/signaling role in which SDF4 engages CXCR4 to drive VEGFD expression via ERK1/2 and p38, with transcriptional induction by CEBPD in cancer-associated fibroblasts.

   Evidence Co-IP, phospho-blots, tube formation and in vivo angiogenesis assays, CEBPD promoter/ChIP analysis

   PMID:33953165

   Open questions at the time

   • Direct SDF4–CXCR4 binding interface not defined
   • How a Golgi-lumenal protein reaches CXCR4 mechanistically unclear

• How sphingolipid composition controls Cab45 TGN retention versus export, and how this is integrated with Ca2+ and phosphorylation signals, remains open.
• Preprint, no direct mechanistic follow-up on SDF4
• Causal link between sphingolipid composition and Cab45 export untested