Lacritin

Lacritin is a 12.3 kDa

Several lacritin splice variants have been detected in Aceview,^[22] from NEIBank EST data.^[23] Lacritin-b (11.1 kDa; pI 5.3) lacks the sequence SIVEKSILTE. Lacritin-c (10.7 kDa; pI 4.6) displays a novel C-terminus that should be incapable of binding syndecan-1, and lacks cell survival activity.^[7]

Splice variants are

Lacritin-dependent mitogenesis is inhibitable by pertussis toxin,.^[18] The implication is that another key element of lacritin targeting specificity is a G-protein-coupled receptor that would presumably form a cell surface targeting complex with SDC1. Involvement of a G-protein coupled receptor would explain the rapidity of lacritin signaling.

Function

Lacritin is a

Artificial depletion of lacritin from normal human tears revealed that tears lacking lacritin are unable to promote the survival of ocular surface cells stressed with inflammatory cytokines.[7] Human dry eye tears also lack this activity. However, dry eye tears supplemented with lacritin are fully protective.^[7] Similarly, tears artificially depleted of lacritin are deficient in bactericidal activity.^[9] The antibody used to deplete lacritin also depletes C-terminal proteoforms.^[25] These observations suggest that among all tear proteins, lacritin may be the master protector.

Dry eye tears are subject to premature collapse, as are normal human tears artificially depleted of C-terminal proteoforms.^[25] In both cases, stability is largely restored by spiking in synthetic lacritin peptides N-94 or N-94/C-6 as proxy C-terminal proteoforms.^[25] Each peptide inserts rapidly into (O-acyl)-omega-hydroxy fatty acid (OAHFA)^[25] thought to reside at the aqueous lipid boundary in tears. OAHFA is the only class of tear lipids apparently downregulated in dry eye.^[34]

Signaling

Lacritin mitogenic, survival and secretion signaling have been studied.

Lacritin mitogenic signaling^[18] follows two pathways:

• Gα_i or Gα_o → PKCα/PLCγ2 → Ca²⁺ → calcineurin → NFATC1
• Gα_i or Gα_o → PKCα/PLCγ2/PLD1 → mTOR

Rapid dephosphorylation of PKCα causes it to transiently move from the cytoplasm to the area of the Golgi apparatus and peripheral nucleus. Here, it forms a complex with PKCα and PLCγ2 from which downstream mTOR and NFAT signaling is initiated.

Lacritin survival signaling is observed when cells are stressed.^[7] Lacritin promotes survival and homeostasis by transiently stimulating autophagy.^[7] The mechanism appears to involve lacritin stimulated acetylation of the transcription factor FOXO3. Acetylated FOXO3 serves as a ligand for the autophagic mediator ATG101. Lacritin also promotes coupling of FOXO1 (that becomes acetylated with stress) with autophagic mediator ATG7. In the absence of lacritin, no coupling is observed.^[7] Thus acetylation alone is likely insufficient for FOXO1-ATG7 ligation, unlike an initial claim.^[35] Lacritin also restores oxidative phosphorylation and other metabolic events to rescue cells from stress.^[7]

Lacritin stimulated secretion of tear proteins lipocalin and lactoferrin from monkey lacrimal acinar cells does not appear to be mediated by Ca²⁺, unlike the agonist carbachol.^[6] When monkey lacrimal acinar cells are stressed with inflammatory cytokines (as occurs in dry eye), carbachol loses its capacity to promote the secretion of lipocalin. However, lacritin stimulates lipocalin secretion even in the presence of stress.^[6]

Distribution

Species

Genomic sequencing assembled by