CHI3L1

Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secreted glycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1 gene.[5][6][7] The name YKL-40 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. YKL-40 is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells, vascular smooth muscle cells, and hepatic stellate cells. The biological function of YKL-40 is unclear. It is not known to have a specific receptor. Its pattern of expression is associated with pathogenic processes related to inflammation, extracellular tissue remodeling, fibrosis and solid carcinomas[8] and asthma.[9]

CHI3L1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCHI3L1, chitinase 3-like 1 (cartilage glycoprotein-39), ASRT7, CGP-39, GP-39, GP39, HC-gp39, HCGP-3P, YKL-40, YKL40, YYL-40, hCGP-39, chitinase 3 like 1, YK-40
External IDsOMIM: 601525 MGI: 1340899 HomoloGene: 55569 GeneCards: CHI3L1
Orthologs
SpeciesHumanMouse
Entrez

1116

12654

Ensembl

ENSG00000133048

ENSMUSG00000064246

UniProt

P36222

Q61362

RefSeq (mRNA)

NM_001276

NM_007695
NM_001374626

RefSeq (protein)

NP_001267
NP_001267.2

NP_031721
NP_001361555

Location (UCSC)Chr 1: 203.18 – 203.19 MbChr 1: 134.18 – 134.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

Chitinases catalyze the hydrolysis of chitin, which is an abundant glycopolymer found in insect exoskeletons and fungal cell walls. The glycoside hydrolase 18 family of chitinases includes eight human family members. This gene encodes a glycoprotein member of the glycosyl hydrolase 18 family. The protein lacks chitinase activity and is secreted by activated macrophages, chondrocytes, neutrophils and synovial cells. The protein is thought to play a role in the process of inflammation and tissue remodeling.[7] YKL-40 lacks chitinase activity due to mutations within the active site (conserved sequence: DXXDXDXE; YKL-40 sequence: DGLDLAWL).[8]

Regulation and mechanism

YKL-40 has been linked to activation of the AKT pro-survival (anti-apoptotic) signaling pathway. YKL-40 promotes angiogenesis through VEGF-dependent and independent pathways.[10]

YKL-40 is a migration factor for primary astrocytes and its expression is controlled by NFI-X3, STAT3, and AP-1.[11]

CHI3l1 is induced by a variety of cancers and in the presence of semaphorin 7A (protein) can inhibit multiple anti-tumor immune system responses. Activating an antiviral immune pathway known as the RIG-like helicase (RLH) has the ability to counter CHI3l1 induction. Cancer cells can offset RLH by stimulating NLRX1. Poly(I:C), an RNA-like molecule, can stimulate RLH activation. RLH activation can also inhibit the expression of receptor IL-13Rα2 and pulmonary metastasis. It stores NK cell accumulation and activation. It augments the expression of IFN-α/β, chemerin and its receptor ChemR23, p-cofilin, LIMK2 and PTEN and inhibiting BRAF and NLRX1 in a MAVS-dependent manner.[12]

Cancer

It is assumed that YKL-40 plays a role in cancer cell proliferation, survival, invasiveness and in the regulation of cell-matrix interactions. It is suggested that YKL-40 is a marker associated with a poorer clinical outcome in genetically defined subgroups of different tumors. YKL-40 was recently introduced into (restricted) clinical practice. A few techniques are available for its detection.[8]

YKL-40 is a Th2 promoting cytokine that is present at high levels in the tumor microenvironment and in the serum of cancer patients.[13][14] Elevated levels of YKL-40 correlate strongly with stage and outcome of various types of cancer, which establish YKL-40 as a biomarker of disease severity.[15] Targeting YKL-40 with neutralizing antibodies is effective as a treatment in animal models of glioblastoma multiforme.[16]

YKL-40 also enhances tumor survival in response to gamma-irradiation.[10]

Alzheimer's disease and neurodegeneration

As Alzheimer's disease progresses, soluble amyloid beta aggregates in the brain can induce the activation of microglia, which triggers synthesis of pro-inflammatory mediators.[17] This leads to increased Chi3l1 expression in astrocytes.[17] There is evidence that YKL-40 levels are elevated in Alzheimer's patients compared to cognitively normal individuals.[17] Elevated levels of YKL-40 mRNA were found in Alzheimer's-inflicted brains in comparison with normal controls.[17] Additionally, YKL-40 is correlated other dementia biomarkers, such as tau proteins and amyloid beta.[17] YKL-40 is being examined as a novel Alzheimer's biomarker quantified in the cerebrospinal fluid or blood.[18]

In Huntington's disease YKL-40 has an increasing trend in cerebrospinal fluid in the later disease stages and correlates highly with symptom severity.[19][20]

References
  1. GRCh38: Ensembl release 89: ENSG00000133048 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000064246 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Hakala BE, White C, Recklies AD (December 1993). "Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family". The Journal of Biological Chemistry. 268 (34): 25803–10. doi:10.1016/S0021-9258(19)74461-5. PMID 8245017.
  6. Rehli M, Krause SW, Andreesen R (July 1997). "Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation". Genomics. 43 (2): 221–5. doi:10.1006/geno.1997.4778. PMID 9244440.
  7. "Entrez Gene: CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39)".
  8. Kazakova MH, Sarafian VS (2009-03-01). "YKL-40--a novel biomarker in clinical practice?". Folia Medica. 51 (1): 5–14. PMID 19437893.
  9. Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, Radford S, Parry RR, Heinzmann A, Deichmann KA, Lester LA, Gern JE, Lemanske RF, Nicolae DL, Elias JA, Chupp GL (April 2008). "Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function". The New England Journal of Medicine. 358 (16): 1682–91. doi:10.1056/NEJMoa0708801. PMC 2629486. PMID 18403759.
  10. Francescone RA, Scully S, Faibish M, Taylor SL, Oh D, Moral L, Yan W, Bentley B, Shao R (April 2011). "Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma". The Journal of Biological Chemistry. 286 (17): 15332–43. doi:10.1074/jbc.M110.212514. PMC 3083166. PMID 21385870.
  11. Singh SK, Bhardwaj R, Wilczynska KM, Dumur CI, Kordula T (November 2011). "A complex of nuclear factor I-X3 and STAT3 regulates astrocyte and glioma migration through the secreted glycoprotein YKL-40". The Journal of Biological Chemistry. 286 (46): 39893–903. doi:10.1074/jbc.M111.257451. PMC 3220556. PMID 21953450.
  12. Ma B, Herzog EL, Moore M, Lee CM, Na SH, Lee CG, Elias JA (May 2016). "RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis". Scientific Reports. 6: 26299. Bibcode:2016NatSR...626299M. doi:10.1038/srep26299. PMC 4873814. PMID 27198666.
  13. Høgdall EV, Ringsholt M, Høgdall CK, Christensen IJ, Johansen JS, Kjaer SK, Blaakaer J, Ostenfeld-Møller L, Price PA, Christensen LH (January 2009). "YKL-40 tissue expression and plasma levels in patients with ovarian cancer". BMC Cancer. 9: 8. doi:10.1186/1471-2407-9-8. PMC 2645422. PMID 19134206.
  14. Bernardi D, Padoan A, Ballin A, Sartori M, Manara R, Scienza R, Plebani M, Della Puppa A (April 2012). "Serum YKL-40 following resection for cerebral glioblastoma". Journal of Neuro-Oncology. 107 (2): 299–305. doi:10.1007/s11060-011-0762-7. PMID 22102082. S2CID 36048348.
  15. Johansen JS, Christensen IJ, Riisbro R, Greenall M, Han C, Price PA, Smith K, Brünner N, Harris AL (July 2003). "High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival". Breast Cancer Research and Treatment. 80 (1): 15–21. doi:10.1023/A:1024431000710. PMID 12889595. S2CID 29295642.
  16. Faibish M, Francescone R, Bentley B, Yan W, Shao R (May 2011). "A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers". Molecular Cancer Therapeutics. 10 (5): 742–51. doi:10.1158/1535-7163.MCT-10-0868. PMC 3091949. PMID 21357475.
  17. Muszyński P, Groblewska M, Kulczyńska-Przybik A, Kułakowska A, Mroczko B (2017-07-31). "YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer's Disease". Current Neuropharmacology. 15 (6): 906–917. doi:10.2174/1570159X15666170208124324. PMC 5652033. PMID 28183245.
  18. Molinuevo JL, Ayton S, Batrla R, Bednar MM, Bittner T, Cummings J, Fagan AM, Hampel H, Mielke MM, Mikulskis A, O'Bryant S, Scheltens P, Sevigny J, Shaw LM, Soares HD, Tong G, Trojanowski JQ, Zetterberg H, Blennow K (December 2018). "Current state of Alzheimer's fluid biomarkers". Acta Neuropathologica. 136 (6): 821–853. doi:10.1007/s00401-018-1932-x. PMC 6280827. PMID 30488277.
  19. Vinther-Jensen, Tua; Budtz-Jørgensen, Esben; Simonsen, Anja H.; Nielsen, Jørgen E.; Hjermind, Lena E. (November 2014). "YKL-40 in cerebrospinal fluid in Huntington's disease--a role in pathology or a nonspecific response to inflammation?". Parkinsonism & Related Disorders. 20 (11): 1301–1303. doi:10.1016/j.parkreldis.2014.08.011. ISSN 1873-5126. PMID 25219973.
  20. Niemelä, Valter; Burman, Joachim; Blennow, Kaj; Zetterberg, Henrik; Larsson, Anders; Sundblom, Jimmy (2018). "Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease". PLOS ONE. 13 (2): e0193492. Bibcode:2018PLoSO..1393492N. doi:10.1371/journal.pone.0193492. ISSN 1932-6203. PMC 5825143. PMID 29474427.

Further reading

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