LMAN2L

LMAN2L (VIPL) is a Ca2+-dependent L-type lectin and ER-resident membrane protein that functions as a cargo recognition factor for high-mannose glycoproteins in the early secretory pathway (PMID:17621594, PMID:18025080). Unlike the cycling lectins ERGIC-53 and VIP36, LMAN2L is a non-cycling ER resident retained by a cytoplasmic di-arginine (RKR/KRFY) signal; mutation of this motif sends the protein to the cell surface (PMID:12609988, PMID:12878160). Its carbohydrate recognition domain selectively binds the deglucosylated Manα1-2Manα1-2Man trimannose of the D1 branch of high-mannose N-glycans in a Ca2+-dependent manner, with binding favored at the neutral pH of the ER lumen and abolished by glucosylation of the outer mannose (PMID:17621594, PMID:18025080). Functionally, LMAN2L supports ER export and trafficking of glycoproteins, including integrin alpha-6 (ITGA6), and is required for STING translocation from the ER to the Golgi upon activation, with its loss diminishing HCMV-induced type I interferon and ISG responses without affecting STING dimerization or TBK1 recruitment (PMID:12878160, PMID:38687323, PMID:42149942). LMAN2L is itself a target of HCMV-driven ERAD: viral pUS2 recruits the host E3 ligases TRC8 or RNF139 with the E2 enzyme UBE2G2 to direct LMAN2L for proteasomal degradation (PMID:38687323, PMID:42149942). A frameshift mutation eliminating the ER retention signal causes plasma-membrane mislocalization and links LMAN2L to brain development (PMID:31020005).

1. 2003 High

   Established that LMAN2L is a distinct, non-cycling ER-resident lectin whose localization depends on a cytoplasmic di-arginine retrieval signal, distinguishing it from cycling family members ERGIC-53 and VIP36.

   Evidence Mutagenesis of the cytoplasmic RKR/KRFY motif with subcellular localization and pulse-chase analysis in cultured cells, replicated by two labs

   PMID:12609988 PMID:12878160

   Open questions at the time

   • Does not identify the retrograde transport machinery reading the di-arginine signal
   • Does not define the physiological glycoprotein cargo at this stage
2. 2003 Medium

   Implicated LMAN2L in early-secretory-pathway regulation and glycoprotein ER export, addressing what cellular process it serves.

   Evidence Overexpression redistributing ERGIC-53 to the ER, plus siRNA knockdown slowing secretion of two glycoproteins in cultured cells

   PMID:12609988 PMID:12878160

   Open questions at the time

   • Secreted glycoprotein cargoes identified only by molecular weight, not molecular identity
   • Mechanistic relationship to ERGIC-53 not resolved
3. 2007 High

   Defined the molecular basis of cargo recognition, showing LMAN2L is a Ca2+-dependent lectin selective for the deglucosylated D1-branch trimannose of high-mannose N-glycans, with pH and glucosylation gating binding.

   Evidence Recombinant soluble LMAN2L analyzed by flow cytometry, SPR, frontal affinity chromatography with a pyridylaminated sugar library, and structure-based CRD mutagenesis

   PMID:17621594 PMID:18025080

   Open questions at the time

   • In vitro glycan binding not directly linked to specific endogenous cargo in cells
   • Crystal structure of LMAN2L itself not reported
4. 2019 Medium

   Connected the ER retention signal to organismal physiology, showing loss of retention causes plasma-membrane mislocalization and links LMAN2L to brain development.

   Evidence Genetic analysis of a dominant frameshift mutation (c.1073delT) with protein localization assay

   PMID:31020005

   Open questions at the time

   • Cellular mechanism connecting mislocalization to neurodevelopmental phenotype unresolved
   • Single study
5. 2024 Medium

   Identified a specific endogenous trafficking cargo and revealed LMAN2L as a viral ERAD target, showing LMAN2L is required for cell-surface ITGA6 and is degraded by HCMV pUS2 via TRC8.

   Evidence Plasma-membrane proteomic profiling, pUS2/TRC8 knockdown and overexpression, and co-immunoprecipitation

   PMID:38687323

   Open questions at the time

   • Direct lectin-glycan interaction with ITGA6 not biochemically demonstrated
   • Single study with limited mechanistic depth
6. 2026 Medium

   Placed LMAN2L in innate antiviral signaling, showing it physically interacts with STING and is essential for STING ER-to-Golgi translocation and downstream interferon responses, and is degraded via pUS2-RNF139-UBE2G2 ERAD.

   Evidence Reciprocal co-immunoprecipitation, co-localization, LMAN2L knockout with STING translocation and IFN/ISG readouts, and E3/E2 identification

   PMID:42149942

   Open questions at the time

   • Whether STING engagement is glycan-dependent via the CRD is not established
   • Single-lab study
   • Distinction between TRC8 and RNF139 as the operative ligase across contexts unresolved

• It remains unknown how LMAN2L's lectin glycan-recognition activity mechanistically couples to selection of specific cargoes such as ITGA6 and STING and to its neurodevelopmental role.
• No structure of LMAN2L CRD bound to physiological cargo
• Recruitment/retrieval machinery for the di-arginine signal not identified
• Glycan-dependence of STING and ITGA6 handling untested