Lacritin

Last updated

LACRT
Identifiers
Aliases LACRT , entrez:90070, lacritin
External IDs OMIM: 607360; HomoloGene: 88949; GeneCards: LACRT; OMA:LACRT - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_033277

n/a

RefSeq (protein)

NP_150593

n/a

Location (UCSC) Chr 12: 54.63 – 54.63 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

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]

Contents

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]

Structure

Lacritin consists of 119 amino acids after cleavage of the N-terminal signal peptide and displays several predicted alpha helices, mostly in the C-terminal half. Of these, the two C-terminal ones have been confirmed by circular dichroism. [18] The most C-terminal alpha helix is amphipathic with hydrophobic and hydrophilic residues on opposite faces. The hydrophobic face is an important syndecan-1 binding element. [17] PONDR (Predictor of Naturally Disordered Regions) [19] predicts that the C-terminal and N-terminal halves are respectively 'ordered' and 'disordered'. 11 - 12 predicted O-glycosylation sites populate the N-terminal half. The C-terminal amphipathic alpha helix is also the site of lacritin's only N-glycosylation site. In 'climatic droplet keratopathy' this site is not glycosylated. [20] Lacritin recombinantly generated in E. coli (no glycosylation) and lacritin in tears (glycosylated) differ in size with respective mobilities of ~18 and ~25 kDa by SDS-PAGE. With a predicted protein core molecular weight of 12.3 kDa, it is possible that mobility is partially retarded by lacritin's amphipathic alpha helices. Predicted pI of lacritin's core protein is 5. [12]

Lacritin is subject to crosslinking by tissue transglutaminase, thereby giving rise to lacritin multimers including dimers and trimers. [21] Crosslinking is initiated within 1 min in vitro, requiring as little as 0.1 nM lacritin. [21] The ~0.6 micro molar level of tissue transglutaminase estimated in human tears is sufficient to promote crosslinking. [21] Crosslinking involves the donors lysine 82 and 85 and the acceptor glutamine 106. [21] Glutamine 106 resides within the amphipathic alpha helix near the C-terminus responsible for binding the N-terminus of syndecan-1. [17] Accordingly, crosslinked lacritin binds syndecan-1 poorly [21] and is inactive.

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 proteoforms. Proteoforms include proteolytically processed forms of lacritin. Top down mass spec sequencing revealed that human tears contain five N- and forty-two different C-terminal lacritin-a proteoforms. [24] Some approximate the bioactive lacritin synthetic peptides 'N-104', [9] 'N-94' and 'N-94/C-6' [25] from lacritin's C-terminus. Protease inhibitor studies suggest that processing of lacritin into C-terminal proteoforms requires a variety of tear proteases including cathepsin B, calpain, alanyl amino peptidase, arginyl aminopeptidase, MMP9, MMP10, cathepsin G, plasma kallikrein, plasmin, thrombin and trypsin. [25] C-terminal proteoforms, like intact lacritin, are selectively deficient in dry eye tears. [25]

Cell targeting

Lacritin targets a restricted group of epithelial cells (including human corneal epithelia), and not fibroblastic, glioma, or lymphoblastic cells. [18] Cell surface proteoglycan syndecan-1 is partly responsible. [16] [17]

Biotinylated cell surface proteins from a lacritin-responsive cell were incubated with lacritin under conditions of physiological salt. Those that bound lacritin were sequenced by mass spectrometry. Few bound. The most prominent was syndecan-1 (SDC1). In confirmatory pull-down assays, binding was not shared with family members syndecan-2 or syndecan-4, [16] indicating that the protein core (and not the negatively charged heparan sulfate side-chains) was the main site of binding. Further analysis narrowed the site to syndecan-1's N-terminal 51 amino acids, [16] and subsequently to the N-terminal sequence GAGAL that is conserved in syndecan-1's from different species. [17] GAGAL promotes the alpha helicity of lacritin's C-terminal amphipathic alpha helix and likely binds to the hydrophobic face. [17] Syndecan-1 binds many growth factors through its long heparan sulfate side-chains. Yet, long heparan sulfate chains interfere with lacritin binding. Since syndecans are always decorated with heparan sulfate, this means that heparanase must be available to partially or completely cleave off heparan sulfate, allowing lacritin to bind. Indeed, no binding was detected from cells lacking heparanase after siRNA depletion. [16] Binding was restored by spiking in exogenous heparanase or heparitinase. [16] Thus, heparanase regulates lacritin function as an 'on-switch'. Exposed 3-O sulfated groups on heparanase-cleaved heparan sulfate [17] (that likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix), and an N-terminal chondroitin sulfate chain (likely also binds to the cationic face) appear to contribute to binding. [17] Point mutagenesis of lacritin has narrowed the ligation site. [17] This novel heparanase mechanism appears at first glance to be poor for ocular health since heparanase release from invading lymphocytes in the corneal stroma is inflammatory. Yet heparanase is a normal secretory product of the corneal epithelium. [26]

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 glycoprotein of the human tear film, and to a lesser extent of saliva, lung lavage [27] and plasma. [28] It is mainly produced by the lacrimal gland. [4] Some lacritin also is produced by the meibomian gland, and also by epithelial cells of the conjunctiva and cornea. [11] The lacritin gene (LACRT) is one of the most transcriptionally regulated genes in the human eye. [29] Functional studies suggest a role in epithelial renewal of some non-germative epithelia. By flowing downstream through ducts, it may generate a 'proliferative field'. [18] Lacritin also promotes secretion [4] (including that of lipocalin-1 and lactoferrin [6] ), cell survival and regeneration of the corneal epithelium after wounding. [8] Three times daily topical treatment with C-terminal lacritin synthetic peptide 'Lacripep' (also known as 'N-94/C-6') at a 4 μM concentration regenerated corneal nerves and the ocular surface epithelium in the mouse Aire-/- dry eye model. [30] This raises the possibility that lacritin may have clinical applications in the treatment of dry eye, the most common eye disease. It also may be beneficial in promoting healing after LASIK or PRK surgery. Recent studies suggest that lacritin monomer is differentially down regulated in not only in dry eye, [31] but also in blepharitis. [32]

Lacritin is an LFU prosecretory mitogen and survival factor with a biphasic dose response that is optimal at 1 - 10 nM for human recombinant lacritin on human cells. [18] Higher human lacritin concentrations are optimal on rat or mouse cells [4] or on rabbit eyes. [14] In a recent phase I/II clinical trial, a 22 μM topical dose of 'Lacripep' applied three times daily was effective at two weeks in primary Sjogren's Syndrome patients with an eye dryness score greater than 60, a score indicative of moderate to severe dry eye. Both corneal fluorescein staining and the symptom of burning/stinging were reduced. In keeping with a biphasic dose response, the 44 μM dose was largely ineffective. [33] A biphasic dose response has a bell-shaped curve, with doses lower or higher than the dose optimum less effective. Other mitogens share this property. [18] However, in secretion assays using monkey lacritin on monkey lacrimal acinar cells, the dose response appears to be sigmoidal with increasing lipocalin or lactoferrin secretion through a narrow 0.1, 0.3 and 1 μM dose range. [6] Lacritin flows downstream from the lacrimal gland through ducts onto the eye.

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:

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. [18] The upstream Gαi or Gαo signaling suggests the involvement of a G-protein-coupled receptor (GPCR). A candidate GPCR is under study. Syndecan-1 likely serves as a co-receptor. Binding lacritin may improve its GPCR affinity.

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 Ensembl reveals the existence of putative lacritin orthologues in other species. [36] Comparative genomic alignment suggests that horse lacritin is most similar to human lacritin among all non-primate sequences examined. [31] Moreover, it is detectable in horse tears by immunoblotting or by ELISA. [37] Antibodies directed to the C-, but not N-, terminus of human lacritin are most effective [37] - in keeping with the predicted conservation of the C-terminal amphipathic alpha helix [37] necessary for cell targeting. [16]

Tissue

Tissue distribution has been examined in humans and monkeys. Lacritin is most highly expressed in the lacrimal gland, including the accessory lacrimal gland of Wolfring. [10] Expression is moderate in salivary glands and slight in mammary (cancer but not or rarely normal), and thyroid glands. [4] [29] [38] [39] The salivary gland expression appears to be attributable to a discrete group of unidentified ductal-like cells. [4] Some lacritin was reported in lung bronchoalveolar lavage [40] and plasma. [28] In lacrimal gland, polarized lacrimal acinar cells appear to be the most prolific lacritin producers, as evidenced by strong staining of secretory granules [4] in keeping with lacritin release after carbachol stimulation. [11] Carbachol-dependent release involves PKC and calcium signaling. [41] Some lacritin is produced by the meibomian gland, and also by epithelial cells of the conjunctiva and cornea [11] that together with lacrimal gland comprise much of the lacrimal functional unit (LFU). Viewed collectively, the LFU is the primary source of lacritin in the body, and the eye the main target. [4]

Disease

Dry eye is the most common eye disease, affecting 5 - 6% of the population. Prevalence rises to 6 - 9.8% in postmenopausal women, [42] and as high as 34% in the elderly. [43] Tears lubricate the lid and are important for the refraction of light. Tears also promote epithelial health. Only a small fraction of the estimated 1543 proteins [44] in tears are differentially deficient or upregulated in dry eye. [31] Lacritin monomer is differentially downregulated in mild to severe aqueous deficient dry eye, [45] and in contact lens-related dry eye. [13] In a larger trial, 95% of tears from patients with aqueous deficient dry eye were lacritin monomer deficient. [46] Two studies that did not differentiate monomer from multimer did note any change of lacritin in dry eye. Topical treatment of eyes of dry eye mice (Aire knockout mouse model of dry eye) restored tearing, and suppressed both corneal staining and the size of inflammatory foci in lacrimal glands. [15] Lacritin monomer deficiency in tears of patients with blepharitis was also reported. [32] Blepharitis is an inflammation of the eyelid often associated with dry eye. [12] In climatic droplet keratopathy , N119 appears to be un-glycosylated. Also a normal breast cancer localization reported by some has not been replicated in Unigene (the 'mammary gland' hit is for breast cancer) and gene array studies, [39] but some breast cancers appear to display elevated expression [39] or LACRT gene amplification. [47] iTRAQ analysis of tears from diabetics at different stages of disease detected relatively more lacritin, lysozyme, lipophilin A, lipocalin 1, immunoglobulin lambda chain and lactotransferrin in tears of patients with diabetic retinopathy. The analysis did not distinguish lacritin monomer from polymer, and proposed the application of all as biomarkers. [48] Tear lacritin monomer is barely detectable in the initial stage of infection by Fusarium solani in fungal keratitis. [49] Also down regulated are tear lipocalin-1 and cystatin S. [49] Fungal keratitis accounts for half of all corneal ulcers in Africa and India [50] [51] [52] - the primary source of blindness in these countries. [53] Phase II clinical trial of 'Lacripep™ in Subjects With Dry Eye Associated With Primary Sjögren's Syndrome' (NCT03226444) [54] is complete. Lacripep™ is lacritin synthetic peptide 'N-94/C-6'.

Related Research Articles

<span class="mw-page-title-main">Tears</span> Clear liquid secreted from glands in eyes of mammals

Tears are a clear liquid secreted by the lacrimal glands found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of tears—basal, reflex, and emotional—vary significantly in composition.

<span class="mw-page-title-main">Cornea</span> Transparent front layer of the eye

The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is approximately 43 dioptres. The cornea can be reshaped by surgical procedures such as LASIK.

<span class="mw-page-title-main">Dry eye syndrome</span> Medical condition of dry eyes

Dry eye syndrome, also known as keratoconjunctivitis sicca, is the condition of having dry eyes. Symptoms include dryness in the eye, irritation, redness, discharge, blurred vision, and easily fatigued eyes. Symptoms range from mild and occasional to severe and continuous. Dry eye syndrome can lead to blurred vision, instability of the tear film, increased risk of damage to the ocular surface such as scarring of the cornea, and changes in the eye including the neurosensory system.

<span class="mw-page-title-main">Meibomian gland</span> Sebaceous glands along the rims of the eyelid

Meibomian glands are sebaceous glands along the rims of the eyelid inside the tarsal plate. They produce meibum, an oily substance that prevents evaporation of the eye's tear film. Meibum prevents tears from spilling onto the cheek, traps them between the oiled edge and the eyeball, and makes the closed lids airtight. There are about 25 such glands on the upper eyelid, and 20 on the lower eyelid.

<span class="mw-page-title-main">Perlecan</span> Mammalian protein found in Homo sapiens

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Syndecan 1</span> Protein which in humans is encoded by the SDC1 gene

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.

<span class="mw-page-title-main">Syndecan</span>

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. they are proteoglycans, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.

<span class="mw-page-title-main">Syndecan-2</span> Protein-coding gene in the species Homo sapiens

Syndecan-2 is a protein that in humans is encoded by the SDC2 gene.

<span class="mw-page-title-main">Heparanase</span> Mammalian protein found in Homo sapiens

Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.

<span class="mw-page-title-main">Syndecan-3</span> Protein-coding gene in the species Homo sapiens

Syndecan-3 is a protein that in humans is encoded by the SDC3 gene.

<span class="mw-page-title-main">Lipocalin 1</span> Protein-coding gene in the species Homo sapiens

Lipocalin-1 is a protein that in humans is encoded by the LCN1 gene.

<span class="mw-page-title-main">CRYBB1</span> Protein-coding gene in the species Homo sapiens

Beta-crystallin B1 is a protein that in humans is encoded by the CRYBB1 gene. Variants in CRYBB1 are associated with autosomal dominant congenital cataract.

<span class="mw-page-title-main">SFRS4</span> Protein-coding gene in the species Homo sapiens

Splicing factor, arginine/serine-rich 4 is a protein that in humans is encoded by the SFRS4 gene.

<span class="mw-page-title-main">VSX1</span> Protein-coding gene in the species Homo sapiens

Visual system homeobox 1 is a protein that in humans is encoded by the VSX1 gene.

<span class="mw-page-title-main">PNISR</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PRR4</span> Protein-coding gene in the species Homo sapiens

Proline-rich protein 4 is a protein that in humans is encoded by the PRR4 gene.

<span class="mw-page-title-main">Pedram Hamrah</span> German-American ophthalmologist

Pedram Hamrah is a German-American ophthalmologist and immunologist. He obtained his M.D. from the University of Cologne, Germany.

<span class="mw-page-title-main">Ocular immune system</span> Immune system of the human eye

The ocular immune system protects the eye from infection and regulates healing processes following injuries. The interior of the eye lacks lymph vessels but is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells. These cells fight off intraocular infections, and intraocular inflammation can manifest as uveitis or retinitis. The cornea of the eye is immunologically a very special tissue. Its constant exposure to the exterior world means that it is vulnerable to a wide range of microorganisms while its moist mucosal surface makes the cornea particularly susceptible to attack. At the same time, its lack of vasculature and relative immune separation from the rest of the body makes immune defense difficult. Lastly, the cornea is a multifunctional tissue. It provides a large part of the eye's refractive power, meaning it has to maintain remarkable transparency, but must also serve as a barrier to keep pathogens from reaching the rest of the eye, similar to function of the dermis and epidermis in keeping underlying tissues protected. Immune reactions within the cornea come from surrounding vascularized tissues as well as innate immune responsive cells that reside within the cornea.

X-linked endothelial corneal dystrophy (XECD) is a rare form of corneal dystrophy described first in 2006, based on a 4-generation family of 60 members with 9 affected males and 35 trait carriers, which led to mapping the XECD locus to Xq25. It manifests as severe corneal opacification or clouding, sometimes congenital, in the form of a ground glass, milky corneal tissue, and moon crater-like changes of corneal endothelium. Trait carriers manifest only endothelial alterations resembling moon craters.

<span class="mw-page-title-main">Meibomian gland dysfunction</span> Medical condition

Meibomian gland dysfunction is a chronic disease of the meibomian glands, which is commonly characterized by obstruction of the end of the duct that delivers the secretion produced by the glands to the eye surface, which prevents the glandular secretion from reaching the ocular surface. The dysfunction could be that the amount of secretion produced may be abnormal. Dysfunction could also be related to the quality of the meibum produced. MGD may result in evaporative dry eye, blepharitis, chalazion, unsealed lid during sleep, and meibomian gland atrophy.

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