Cingulin-like 1

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Cingulin-like 1, also known as paracingulin or junction-associated-coiled-coil protein (JACOP), is a protein which is encoded by the CGNL1 gene.[1][2][3][4][5]

The paracingulin polypeptide comprises a globular N-terminal "head" domain and an α-helical C-terminal domain which is presumed to form a coiled-coil dimer. Paracingulin is a paralog of cingulin that arose probably from gene duplication. The CGNL1 gene is conserved among different vertebrate species and has not been so far identified in invertebrates.[4][6] The homology search highlights that paracingulin and cingulin have 39% identity in the rod tail sequences. They possess also two highly homologous regions in their N-terminus “head” domain including the ZIM region (ZO-1 interaction motif).[4]

The etymology of the name cingulin comes from the Latin "cingere" which means « to form a belt around ». Both, cingulin and paracingulin are localized in the cytoplasmic face of tight junctions (TJ).[3] The prefix « para » refers to “paralog”. However, immunoelectron microscopy indicates that paracingulin is not only localized in the TJ but also in the adherens junctions (AJ) depending on tissue type.[5] TJ and AJ together form the apical junctional complex (AJC) of vertebrate epithelial cells. The proteins present in this complex play a role in many cellular processes i.e., in the adhesion and barrier function of epithelia, the organization and dynamics of the cytoskeleton, as well as the regulation of Rho-GTPase family.

Discovery

CGNL1 was originally discovered in 1997 as a 155 kDa protein localized at epithelial and endothelial cell-cell junctions by using a new monoclonal antibody produced through immunization with a cell-cell junction enriched in plasma membrane fraction from chick liver.[7] Subsequently, cloning and sequencing of the CGNL1 gene identified the similarity to cingulin.[4][6]

Localization

Paracingulin has been localized in epithelial and in endothelial tissues by immunofluorescence and immunoelectron microscopy. It localizes at junctions of epithelial cells, both at tight junctions and adherens junctions depending on cell tissue:[4]

  • In kidney tissue, paracingulin is localized both at TJs and AJs.
  • In liver tissue, immunofluorescence experiments show junctional and apical localizations, whereas immunoelectron microscopy shows an exclusive TJ localization.
  • In intestinal tissue, paracingulin is associated with non junctional actin filaments in the basal region of the cells.
  • In cultured fibroblasts, a non junctional localization of paracingulin along actin stress fibers has also been observed in fibroblasts when exogenous paracingulin is expressed.

Paracingulin can also be found in non-junctional sites in some tissues for example in the cytoplasm and at the base of the cells.[4][8] Finally, in isolated cells, paracingulin is localized at the cell periphery, unlike cingulin and ZO-1 and was detected in the leading edges of migrating cells.[8]

Structure and interactions

Human paracingulin is composed of 1302 amino acids with a predicted molecular weight of 148 kDa.[4][9] Sequence similarity searches show that paracingulin is most similar to cingulin[9] and comprises three major structural domains: A globular head (residues 1-598), a central coiled-coil rod domain (residues 599-1262) and a small globular tail domain at its C-terminus (residues 1263-1302). It is also predicted that this protein form a dimer through its coiled-coil rod domain.[9][10] Both head and rod-tail domains associate with epithelial tight junctions when transfected into epithelial cells.[4] Additionally, the head domain interacts with actin filaments independently of the Rod domain although the association is stabilized when the head is part of the full-length molecule.[5] As its homologue cingulin, the head domain of paracingulin has a ZO-1 Interacting Motif (ZIM) that is involved in its junctional recruitment to tight junctions through ZO-1.[11] Also, the head domain interacts with PLEKHA7, a protein present in the zonula adhaerens of epithelial cells, and this interaction is important for CGNL1 recruitment to adherens junctions. In addition the paracingulin interacts with the Rho GEF GEF-H1, the Rac1 GEF Tiam1 Tiam1, and it forms a complex with[6][11] CD2AP and SH3BP1.[12] Association of paracingulin with the apical junctional complex is a highly dynamic process, and requires the integrity of both microtubule and actin cytoskeleton.[8]

Paracingulin interacts with cingulin and PLEKHA7 (as revealed by a yeast two-hybrid screen) as well as ZO-1, this latter through the ZIM region.[11] JACOP is recruited to the TJ through interaction with ZO-1 (TJ-associated plaque protein, belonging to the membrane-associated guanylate kinase family)[11]but is recruited to the AJ via interaction of it N-terminus head with PLEKHA7.

Unlike cingulin, paracingulin associates with actin filaments[4][5] in different types of culture cells and its localization at the apical junctional complex is perturbed by treatment with the microtubule drug nocodazole.[8] Paracingulin regulates the activity of Rho family GTPases like RhoA, Rac1 and Cdc42 by interacting with their respective GEFs (guanine nucleotide exchange factor), GEF-H1, Tiam1 and GAPs[12] to the epithelial junction during the formation of cell-cell junction.[6] The regulation of these GTPases is crucial for cell growth, activation of kinases and cytoskeletal organization.

Function

The function of paracingulin has been mainly studied using knockdown approaches. Paracingulin locally regulates the activity of some members of the Rho GTPases family at the apical junctional region, thus participating in junction assembly and maintenance. Depletion of paracingulin by shRNA in cultured kidney cells (MDCK) does not alter tight or adherens junctions organization. However, it leads to increased levels of the mRNA encoding the tight junction proteins ZO-3 and claudin-2, as well as increased levels of the ZO-3 protein,[6] whereas when combined with the depletion of cingulin, it causes a decrease in the expression of these proteins.[13]

Paracingulin plays also a role in the initial phase of junction assembly. Indeed, its depletion in the experimental model of “calcium switch”, which allows the study of Calcium-dependant junction formation, causes delayed tight junction assembly, correlating with a decrease in the Rac1 GTPase activity.[5] The rod domain of the protein is critically involved in this Rac1-dependent regulation of junction assembly, as its overexpression mimicks the effect of paracingulin depletion;[8] by the way, this also suggests that the head domain somehow prevents its action within the full-length protein. The phenotype can be rescued by an increase in Rac1 activity driven by overexpression of the GEF Tiam1, but not by increased RhoA activity. Indeed, paracingulin can interact with and thus recruit Tiam1 to the junction, allowing the local activation of Rac1[6] Both paracingulin depletion and overexpression experiments also led to the conclusion that it also interacts with and recruits SH3BP1, which is an inactivator of the Rho GTPases Cdc42 and Rac1 involved in epithelial junction formation in association with the filamentous actin-capping protein CapZ, by controlling actin-driven membrane remodeling.[12] Paracingulin thus really acts as an adaptator for Rho GTPase regulators at the apical junctional region, and possibly at other cellular sites, because of its extra-junctional localization. In addition, cingulin and paracingulin have similar dynamics, partially overlapping subcellular localizations, and distinct interactions with the actin and microtubule cytoskeletons.[5]

Homolog

The CGNL1 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, and zebrafish. Cingulin-like 1 and cingulin are homologous proteins with a good degree of similarity in sequence and domain organization.[4][8][9]

The mouse homolog of CGNL1 has been designated JACOP (junction-associated coiled-coil protein). JACOP is recruited to the junctional complex in epithelial cells and to cell-cell contacts in fibroblasts. It has been suggested that JACOP is involved in anchoring cell-cell contacts to actin-based cytoskeletons within cells.[4]

Diseases

Paracingulin has been so far implicated in two diseases:

  1. The aromatase excess syndrome: Heterozygous chromosomal inversion brings a cryptic aromatase promoter containing a portion of the CGNL1 promoter into a position immediately to the 5-prime of the coding region of cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) gene.[14][15]
  2. Schizophrenia: The CGNL1 locus is one of the three loci which have been reported to be implicated in increased susceptibility to schizophrenia through the duplications at 1p36.33.[16]

References

  1. ↑ Nagase T, Kikuno R, Hattori A, Kondo Y, Okumura K, Ohara O (December 2000). "Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (6): 347–355. doi:10.1093/dnares/7.6.347. PMID 11214970.
  2. ↑ "Entrez Gene CGNL1 cingulin-like 1 [Homo sapiens (human)]".
  3. ↑ 3.0 3.1 Citi S, Pulimeno P, Paschoud S (June 2012). "Cingulin, paracingulin, and PLEKHA7: signaling and cytoskeletal adaptors at the apical junctional complex". Annals of the New York Academy of Science. 1257: 125–132. doi:10.1111/j.1749-6632.2012.06506.x. PMID 22671598.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 Ohnishi H, Nakahara T, Furuse K, Sasaki H, Tsukita S, Furuse M (October 2004). "JACOP, a novel plaque protein localizing at the apical junctional complex with sequence similarity to cingulin". Journal of Biological Chemistry. 279 (44): 46014–46022. doi:10.1074/jbc.M402616200. PMID 15292197.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Paschoud S, Guillemot L, Citi S (April 2012). "Distinct domains of paracingulin are involved in its targeting to the actin cytoskeleton and regulation of apical junction assembly". Journal of Biological Chemistry. 287 (16): 13159–13169. doi:10.1074/jbc.M111.315622. PMC 3340007. PMID 22315225.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Guillemot L, Paschoud S, Jond L, Foglia A, Citi S (October 2008). "Paracingulin regulates the activity of Rac1 and RhoA GTPases by recruiting Tiam1 and GEF-H1 to epithelial junctions". Molecular Biology of the Cell. 19 (10): 4442–4453. doi:10.1091/mbc.E08-06-0558. PMC 2555940. PMID 18653465.
  7. ↑ Hirase T, Furuse M, Tsukita S (February 1997). "A 155-kDa undercoat-constitutive protein of cell-to-cell adherens junctions". European Journal of Cell Biology. 72 (2): 174–181. PMID 9157014.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Paschoud S, Yu D, Pulimeno P, Jond L, Turner JR, Citi S (February 2011). "Cingulin and paracingulin show similar dynamic behaviour, but are recruited independently to junctions". Molecular Membrane Biology. 28 (2): 123–35. doi:10.3109/09687688.2010.538937. PMC 4336546. PMID 21166484.
  9. ↑ 9.0 9.1 9.2 9.3 Guillemot L, Citi S (2006). "Cingulin, a Cytoskeleton-Associated Protein of the Tight Junction". In Gonzalez-Mariscal L. Tight junctions. Georgetown, Texas: Landes Bioscience/Eurekah.com. pp. 54–63. ISBN 978-0-387-36673-9.
  10. ↑ Guillemot L, Paschoud S, Pulimeno P, Foglia A, Citi S (March 2008). "The cytoplasmic plaque of tight junctions: a scaffolding and signalling center". Biochimica et Biophysica Acta. 1778 (3): 601–613. doi:10.1016/j.bbamem.2007.09.032. PMID 18339298.
  11. ↑ 11.0 11.1 11.2 11.3 Pulimeno P, Paschoud S, Citi S (May 13, 2011). "A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells". Journal of Biological Chemistry. 286 (19): 16743–16750. doi:10.1074/jbc.M111.230862. PMC 3089516. PMID 21454477.
  12. ↑ 12.0 12.1 12.2 Elbediwy A, Zihni C, Terry SJ, Clark P, Matter K, Balda MS (August 2012). "Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex". Journal of Cell Biology. 198 (4): 677–693. doi:10.1083/jcb.201202094. PMC 3514035. PMID 22891260.
  13. ↑ Guillemot L, Spadaro D, Citi S (2013). Koval M, ed. "The junctional proteins cingulin and paracingulin modulate the expression of tight junction protein genes through GATA-4". PLoS ONE. 8 (2): e55873. doi:10.1371/journal.pone.0055873. PMC 3567034. PMID 23409073.
  14. ↑ Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M (September 2003). "The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters". Journal of Steroid Biochemistry and Molecular Biology. 86 (3–5): 219–224. doi:10.1016/S0960-0760(03)00359-5. PMID 14623514.
  15. ↑ Demura M, Bulun SE (February 2008). "CpG dinucleotide methylation of the CYP19 I.3/II promoter modulates cAMP-stimulated aromatase activity". Molecular and Cellular Endocrinology. 283 (1–2): 127–132. doi:10.1016/j.mce.2007.12.003. PMID 18201819.
  16. ↑ Rees E, Walters JT, Chambert KD, O'Dushlaine C, Szatkiewicz J, Richards AL, Georgieva L, Mahoney-Davies G, Legge SE, Moran JL, Genovese G, Levinson D, Morris DW, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A, Sklar P, Hultman C, Pato C, Pato M, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJ, Kirov G (November 2013). "CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1". Human Molecular Genetics. 23 (6): 1669–1676. doi:10.1093/hmg/ddt540. PMC 3929090. PMID 24163246.

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