Articles

Identification of Key Genes and Pathways in RBCK1 Deficient patients by Gene Expression Profiling

Abstract

HOIL-1/RBCK1 deficiency is a new autosomal receive disorder with unstable cellular responses to pro-inflammatory cytokines, resulting in auto-inflammation, pyogenic bacterial disease, as well as the development of muscular amylopectinosis. This study explored the molecular mechanisms of RBCK1 deficiency with integrated bioinformatics analyses of the feature genes and the correlative gene functions. The expression profile of GSE24519 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between RBCK1, MYDK88, NEMO deficient fibroblast, and healthy fibroblast specimens were identified. Gene ontology (GO) enrichment analysis on gene functions and the Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis were performed by using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape was used to visualize the protein-protein interaction (PPI) of these DEGs. GO analysis revealed that the “Skeletal system development, Extracellular matrix organization, Positive regulation of cell migration, Negative regulation of canonical Wnt signaling pathway, Cell adhesion, Angiogenesis and Negative regulation of BMP signaling pathway, Serine-type carboxypeptidase activity, Polysaccharide binding, Calcium ion binding, frizzled binding, Neuropilin binding, and cell adhesion molecule binding, extracellular exosome, extracellular space, extracellular region, lysosomal lumen, endoplasmic reticulum lumen, cell surface and focal adhesion to BP, MF, and CC, respectively. The KEGG pathway analysis showed that the complement and coagulation cascade, ECM receptor interactions, PI3K- Akt signaling pathway, PPAR signaling pathway, TGF-beta signaling pathway, Pathway in Cancer, Viral carcinogenesis and Focal adhesion pathway were closely associated with RBCK1 deficiency occurrence. Importantly, TK1, AURKB, CDCA2, UBE2C, KIFC1, CEP55, CDCA3, GINS2, MCM6, and CDC45 were predicted to be significantly related to RCBK1 deficiency. Our discovery provides a registry of genes and pathways that are disrupted in RCBK1, which will enhance in understanding the pathogenesis of RBCK1 deficiency and other innate immunodeficiency diseases. This study has the potential to be used in the clinic for diagnosis and targeted therapy of RCBKI and other innate immunodeficiencies in the future.

1. Sasaki Y & Iwai K. Crucial Role of Linear Ubiquitin Chain Assembly Complex–Mediated Inhibition of Programmed Cell Death in TLR4-Mediated B cell Responses and B1b Cell Development. The Journal of Immunology 2018; 200(10): 3438–3449. doi:10.4049/jimmunol.1701526

2. Komander D, Rape M. The ubiquitin code. Annu. Rev. Biochem.2012; 81: 203–229

3. Bondos SE, Tan,X.X, and Matthews KS. Physical and genetic interactions link hox function with diverse transcription factors and cell signaling proteins. Mol. Cell Proteomics 2006; 5: 824–834.

4. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011; 471:591–596. doi: 10.1038/nature09816. [PubMed] [CrossRef] [Google Scholar]

5. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, Abhyankar A, Israel L, Trevejo-Nunez G, Bogunovic D, et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol. 2012; 13:1178–1186. doi: 10.1038/ni.2457.

6. Nilsson J, Schoser B, Laforet P, Kalev O, Lindberg C, Romero NB, Davila Lopez M, Akman HO, Wahbi K, Iglseder S, et al. Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann Neurol. 2013; 74:914–919. doi: 10.1002/ana.23963. [PubMed] [CrossRef] [Google Scholar]

7. Lambert,B, Vandeputte J, Remacle,S, Bergiers I, Simonis N, Twizere JC, Vidal M and Rezsohazy R. Protein interactions of the transcription factor Hoxa1. BMC Dev Biol 2012; 12 (1): 29.


8. Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka,K., Nakano,H. and Iwai,K..SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature, 2011; 471:633–636.

9. Berghe, TV, Linkermann A, Jouan-Lanhouet S, Walczak H & Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol Cell Biol 2014; 15: 135–147.

10. Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 2009; 36: 831–844.

11. Tian,Y., Zhang,Y., Zhong,B., Wang,Y.Y., Diao,F.C., Wang,R.P., Zhang,M., Chen,D.Y., Zhai,Z.H. and Shu,H.B. RBCK1 negatively regulates tumor necrosis factor and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation. J Biol Chem 2007; 282: 16776–16782.

12. Ghosh S, May MJ and Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16, 225–260.



13. Aksentijevich I, Zhou Q. NF-kappaB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol 2017; 8:399. doi: 10.3389/fimmu.2017. 00399

14. Oda H, Beck DB, Kuehn HS, Sampaio Moura N, Hoffmann P, Ibarra M, Aksentijevich, I. Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC. Frontiers in Immunology, (2019); 10. doi:10.3389/fimmu.2019.00479

15. Paraguison,R.C., Higaki,K., Sakamoto,Y., Hashimoto,O., Miyake,N., Matsumoto,H., Yamamoto,K., Sasaki,T., Kato,N. and Nanba,E.. Polyhistidine tract expansions in HOXA1 result in intranuclear aggregation and increased cell death. Biochem Biophys. Res Commun 2005; 336: 1033–1039.


16. Liu J, Wang B, Chen X, Li H, Wang J, Cheng L, Ma X and Gao B. HOXA1 gene is not potentially related to ventricular septal defect in Chinese children. Pediatr Cardiol 2013; 34, 226–230.

17. Baeuerle PA and Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 1988; 242:540–546.

18. Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N, Hazen M, et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med 2015; 212:939–51. doi: 10.1084/jem.201 41130

19. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 2012; 13:1178–86. doi: 10.1038/ni.2457

20. Dubois SM, Alexia C, Wu Y, Leclair HM, Leveau C, Schol E et al. A catalytic-independent role for the LUBAC in NF-kappaB activation upon antigen receptor engagement and in lymphoma cells. Blood 2014; 123:2199–203. doi: 10.1182/blood-2013-05- 504019

21. Okamura K, Kitamura A, Sasaki Y, Chung DH, Kagami S, Iwai K, et al. Survival of mature T cells depends on signaling through HOIP. Sci Rep 2016; 6:36135. doi: 10.1038/srep 36135

22. Nilsson J, Schoser B, Laforet P, Kalev O, Lindberg C, Romero NB, et al. Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann Neurol 2013; 74:914–9. doi: 10.1002/ana. 23963

23. Morpheus, https://software.broadinstitute.org/morpheus.

24. Huang D, Sherman BT, Tan Q, Collins JR, Alvord WG, Roayaei J, Lempicki RA. “The DAVID gene functional classification tool: a novel biological module-centric algorithm to functionally analyze large gene lists,” Genome Biology, 2007; 8 (9): articleR183,


25. Gene Ontology Consortium. The gene ontology (GO) project in 2006. Nucleic Acids Res. (2006) 34: D322-D326.

26. Kanehisa M, Susumu G. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28: 27-30. [Crossref]


27. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, von Mering C. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019 Jan; 47:D607-613.

28. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks Genome Research 2003 Nov; 13(11):2498-504
29. Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 2003;4:2

30. Maere S, Heymans K and Kuiper M: BiNGO: A Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 2005. 21: 3448 3449.


31. Zhou et al. Nature Commun 2019 10(1):1523 (Metaphase)

32. Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository Nucleic Acids Res 2002 Jan 1;30(1):207-10

33. Brugge J, Hung MC, Mills GB.A new mutational AKTivation in the PI3K pathway. Cancer Cell 2007; 12(2): 104–7.

34. King D, Yeomanson D, Bryant HE. PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol. 2015; 37: 245-251.


35. Jung S, Gámez-Díaz L, Proietti M & Grimbacher B. “Immune TOR-opathies,” a Novel Disease Entity in Clinical Immunology. FIMMU 2018 9. doi:10.3389/fimmu.2018.00966
36. Soliman G. The Role of Mechanistic Target of Rapamycin (mTOR) Complexes Signaling in the Immune Responses. Nutrients 2013; 5(6): 2231–2257. doi:10.3390/nu5062231

37. Ghoneum A and Said N. PI3K-AKT-mTOR and NFκB Pathways in Ovarian Cancer: Implications for Targeted Therapeutics. Cancers 2019; 11(7): 949. doi:10.3390/cancers11070949


38. Mace EM. Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency. FIMMU 2018 9. doi:10.3389/fimmu.2018.00445.

39. Walsh CM & Fruman DA. Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling. Journal of Clinical Investigation 2014; 124(9): 3688–3690. doi:10.1172/jci77198


40. Busca A, Saxena M, Iqbal S, Angel J & Kumar A. PI3K/Akt regulates survival during differentiation of human macrophages by maintaining NF-κB-dependent expression of antiapoptotic Bcl-xL. Journal of Leukocyte Biology 2014; 96(6): 1011–1022. doi:10.1189/jlb.1a0414-212r


41. C.L. Lucas, A. Chandra, S. Nejentsev, A.M. Condliffe, K. Okkenhaug. PI3Kδ and primary immunodeficiencies Nat. Rev. Immunol., 16 (2016), pp. 702-714.

42. Bright JJ, Kanakasabai S, Chearwae W and Chakraborty, S. PPAR Regulation of Inflammatory Signaling in CNS Diseases. PPAR Research 2008; 1–12. doi:10.1155/2008/658520

43. Le Menn, G, & Neels, J. Regulation of Immune Cell Function by PPARs and the Connection with Metabolic and Neurodegenerative Diseases. International Journal of Molecular Sciences 2018; 19(6): 1575. doi:10.3390/ijms19061575

44. Daynes RA & Jones DC. Emerging roles of PPARS in inflammation and immunity. Nature Reviews Immunology 2002; 2(10): 748–759. doi:10.1038/nri912

45. Hanley TM, Blay Puryear W, Gummuluru S & Viglianti GA. PPARγ and LXR Signaling Inhibit Dendritic Cell-Mediated HIV-1 Capture and trans-Infection. PLoS Pathogens 2010; 6(7): e1000981. doi:10.1371/journal.ppat.1000981


46. Batlle E & Massagué J. Transforming Growth Factor-β Signaling in Immunity and Cancer. Immunity 2019; 50(4): 924–940. doi:10.1016/j.immuni.2019.03.024

47. Rosenzweig SD & Holland SM. Phagocyte immunodeficiencies and their infections. Journal of Allergy and Clinical Immunology 2004; 113(4): 620–626. doi:10.1016/j.jaci.2004.02.001

48. McNeil JC. Staphylococcus aureus - antimicrobial resistance and the immunocompromised child. Infection and drug resistance 2014; 7: 117–127. https://doi.org/10.2147/IDR.S39639


49. Urban BC, David JR. Inhibition of T cell Function during Malaria: Implications for Immunology and Vaccinology. J Exp Med. 2003; 197 (2): 137–141.


50. Stelzer G, Rosen R, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Iny Stein T, Nudel R, Lieder I, Mazor Y, Kaplan S, Dahary D, Warshawsky D, Guan - Golan Y, Kohn A, Rappaport N, Safran M, and Lancet D. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analysis , Current Protocols in Bioinformatics 2016; 54:1.30.1 - 1.30.33.doi: 10.1002 / cpbi.5

51. Dastsooz H, Cereda M, Donna D & Oliviero SA. Comprehensive Bioinformatics Analysis of UBE2C in Cancers. International Journal of Molecular Sciences 2019; 20(9): 2228. doi:10.3390/ijms20092228

52. Wang R, Song Y, Liu X, Wang Q, Wang Y, Li L, Zhang Q. UBE2C induces EMT through Wnt/β-catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A. International Journal of Oncology 2017; 50(4): 1116–1126. doi:10.3892/ijo.2017.3880

53. Cai X. & Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 2007; 13(3): 313–316. doi:10.1261/rna.351707.

54. Atianand MK. & Fitzgerald KA. Long non-coding RNAs and control of gene expression in the immune system. Trends in Molecular Medicine 2014; 20(11): 623–631. doi:10.1016/j.molmed.2014.09.002

55. Inoue M, Yamada J, Aomatsu-Kikuchi E, Satoh K, Kondo H, Ishisaki A & Chosa N. SCRG1 suppresses LPS-induced CCL22 production through ERK1/2 activation in mouse macrophage Raw264.7 cells. Molecular Medicine Reports 2017; 15(6): 4069–4076. doi:10.3892/mmr.2017.6492

56. Touraine JL & Bétuel H. Immunodeficiency diseases and expression of HLA antigens. Human Immunology 1981; 2(2): 147–153. doi:10.1016/0198-8859(81)90061-6

57. https://panelapp.genomicsengland.co.uk/panels/398/gene/CFD/#!).

58. Cottineau J, Kottemann, MC, Lach FP, KangYH et al. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. The Journal of clinical investigation 2017; 127(5): 1991–2006. https://doi.org/10.1172/JCI90727


59. Stein EV, Miller TW, Ivins-O’Keefe K, Kaur S & Roberts DD. Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1β Production and Activation through CD47. Scientific Reports 2016; 6(1).:doi:10.1038/srep19684

60. Nagarkar DR, Ramirez-Carrozzi, V, Choy DF, Lee K, Soriano R, Jia G, Arron JR. IL-13 mediates IL-33–dependent mast cell and type 2 innate lymphoid cell effects on bronchial epithelial cells. Journal of Allergy and Clinical Immunology 2015; 136(1): 202–205. doi:10.1016/j.jaci.2015.01.036

61. Punwani D, Pelz, B, Yu J, Arva NC, Schafernak K, Kondratowicz K, Makhija M Puck JM. Coronin-1A: immune deficiency in humans and mice. Journal of clinical immunology 2015; 35(2): 100–107. https://doi.org/10.1007/s10875-015-0130-z
Files
IssueVol 59, No 5 (2021) QRcode
SectionArticles
Published2021-07-05
DOI https://doi.org/10.18502/acta.v59i5.6661
Keywords
Primary immunodeficiency RBCK1 deficiency Differential expressed genes Key pathways Hub genes Microarray

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Shinwari K, A. Bolkov M, A. Tuzankina I, A. Chereshnev V. Identification of Key Genes and Pathways in RBCK1 Deficient patients by Gene Expression Profiling. Acta Med Iran. 59(5):265-279.