Lacritin
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Lacritin is a 12.3 kDa glycoprotein encoded in humans by the LACRT gene.[3][4] Lacritin's discovery emerged from a screen for factors that stimulate tear protein secretion.[4][5] Lacritin is a secreted protein found in tears and saliva. Lacritin also promotes tear secretion,[4][6] the proliferation[4] and survival of epithelial cells,[7] and corneal wound healing[8] Lacritin is thus a multifunctional prosecretory mitogen with cell survival activity. Natural or bacterial cleavage of lacritin releases a C-terminal fragment that is bactericidal.[9]
Most lacritin is produced by the lacrimal gland,[4] including the accessory lacrimal gland of Wolfring.[10] Some lacritin is produced by the meibomian gland, and by epithelial cells of the conjunctiva and cornea.[11] Together these epithelia comprise much of the lacrimal functional unit (LFU). Dry eye is the most common disease of the LFU. A growing number of studies suggest that lacritin may be differentially downregulated in dry eye,[12] including contact lens-related dry eye.[13] Topical lacritin promotes tearing in rabbit preclinical studies.[14] In the Aire knockout mouse model of dry eye (considered similar to human Sjogren's syndrome), topical lacritin restores pilocarpine-induced tearing, largely eliminates lissamine green staining and reduces the size of inflammatory foci in the lacrimal gland.[15]
Lacritin cell targeting is dependent on the cell surface heparan sulfate proteoglycan syndecan-1 (SDC1).[16][17] Binding utilizes an enzyme-regulated 'off-on' switch in which active epithelial heparanase (HPSE) cleaves off heparan sulfate to expose a binding site in the N-terminal region of syndecan-1's core protein.[16] A G-protein-coupled receptor (GPCR) then appears to be ligated.[18] Targeted cells signal to NFAT and mTOR[18] if conditions are suitable for proliferation, or to AKT and FOXO3 under conditions of stress.[7]