SEC14L1

SEC14L1 is a multi-domain cytosolic protein containing CRAL-TRIO, PRELI-MSF1, and GOLD domains that functions as a negative regulator of RIG-I-mediated innate antiviral signaling (PMID:23843640). SEC14L1 binds the N-terminal CARD domain of RIG-I through its CRAL-TRIO and PRELI-MSF1 domains, competing with the downstream adaptor MAVS/VISA for RIG-I binding and thereby attenuating interferon-β induction and enhancing viral replication when overexpressed (PMID:23843640). Through its GOLD domain, SEC14L1 also interacts with the vesicular acetylcholine transporter (VAChT) and the high-affinity choline transporter (CHT1), redistributing from the cytosol to vesicular compartments upon transporter co-expression and modestly suppressing choline transport activity (PMID:17092608).

1. 1996 Low

   Cloning of SEC14L1 established it as a ubiquitously expressed human protein with homology to yeast Sec14p and lipid-binding proteins, suggesting involvement in intracellular transport, but no direct functional data existed.

   Evidence cDNA cloning, sequence homology analysis, FISH mapping, and Northern blot expression profiling

   PMID:8697811

   Open questions at the time

   • No direct biochemical activity demonstrated; role inferred from sequence homology alone
   • No ligand or binding partner identified
   • Subcellular localization not experimentally determined beyond tissue expression
2. 2001 Low

   Detailed genomic characterization identified the CRAL/TRIO domain and two splice variants, linking SEC14L1 structurally to lipid-binding/transfer proteins such as TTPA and CRALBP, but lipid-binding activity was not tested.

   Evidence Genomic cloning, exon mapping, RT-PCR, and domain identification by sequence homology

   PMID:11707779

   Open questions at the time

   • No biochemical validation of lipid binding or transfer activity
   • Functional significance of splice variants not determined
   • No interacting partners identified
3. 2006 Medium

   Identification of VAChT and CHT1 as physical interaction partners provided the first direct functional context for SEC14L1, revealing that its GOLD domain mediates cholinergic transporter binding and that co-expression causes cytosol-to-vesicle redistribution with modest suppression of choline uptake.

   Evidence Yeast two-hybrid screen of brain cDNA library, co-immunoprecipitation in mammalian cells, immunofluorescence, and choline transport assay

   PMID:17092608

   Open questions at the time

   • Physiological relevance of the modest transport suppression in neurons not tested in vivo
   • Mechanism by which SEC14L1 inhibits CHT1 activity is unclear
   • No loss-of-function experiment for cholinergic phenotype
4. 2013 High

   Demonstration that SEC14L1 directly binds the RIG-I CARD domain and competes with MAVS/VISA established SEC14L1 as a negative regulator of innate antiviral signaling, with domain mapping showing the CRAL-TRIO and PRELI-MSF1 domains — but not the GOLD domain — are required for this inhibitory function.

   Evidence Yeast two-hybrid, endogenous and transfected co-immunoprecipitation, IFN-β reporter assays, siRNA knockdown with viral replication readouts, and deletion mutagenesis

   PMID:23843640

   Open questions at the time

   • Structural basis of CARD domain recognition by CRAL-TRIO/PRELI-MSF1 domains is unknown
   • In vivo role in antiviral immunity not tested in knockout animal models
   • Whether lipid binding by the CRAL-TRIO domain regulates its RIG-I inhibitory function is untested

• It remains unknown whether the lipid-binding capacity predicted by the CRAL-TRIO domain is biochemically real and whether lipid occupancy modulates the dual functions of SEC14L1 in innate immunity and cholinergic signaling.
• No lipid-binding or transfer activity has been biochemically demonstrated
• No knockout or in vivo model exists to define physiological function
• Relationship between cholinergic transporter interaction and antiviral signaling function is unexplored