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UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development


Protein modification by Ubiquitin (Ub) and Ubiquitin-like proteins (Ubl) plays pivotal roles in a wide range of cellular functions and signaling pathways. The Ufm1 conjugation system is a novel ubiquitin-like system, yet its biological functions and working mechanism remains poorly understood. UFBP1 is a putative Ufm1 target that has been implicated in several signaling pathways but little is known regarding its in vivo function. In this report, by using multiple knockout mouse models, we demonstrate that UFBP1 is essential for murine development and blood cell development. While germ-line deletion of UFBP1 caused defective red blood cell development and embryonic lethality, somatic ablation of UFBP1 impaired production of mature red blood cells and other types of hematopoietic cells. We found that depletion of UFBP1 led to elevated stress in the endoplasmic reticulum that in turn caused cell death of hematopoietic stem cells. Furthermore, UFBP1 deficiency diminished expression of key transcription factors essential for red blood cell development. Taken together, our study provides strong genetic evidence for the essential role of UFBP1 as well as other components of the Ufm1 system in hematopoietic development. Therefore, the ufmylation pathway may represent a novel therapeutic target in treatment of blood diseases.


Vyšlo v časopise: UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development. PLoS Genet 11(11): e32767. doi:10.1371/journal.pgen.1005643
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005643

Souhrn

Protein modification by Ubiquitin (Ub) and Ubiquitin-like proteins (Ubl) plays pivotal roles in a wide range of cellular functions and signaling pathways. The Ufm1 conjugation system is a novel ubiquitin-like system, yet its biological functions and working mechanism remains poorly understood. UFBP1 is a putative Ufm1 target that has been implicated in several signaling pathways but little is known regarding its in vivo function. In this report, by using multiple knockout mouse models, we demonstrate that UFBP1 is essential for murine development and blood cell development. While germ-line deletion of UFBP1 caused defective red blood cell development and embryonic lethality, somatic ablation of UFBP1 impaired production of mature red blood cells and other types of hematopoietic cells. We found that depletion of UFBP1 led to elevated stress in the endoplasmic reticulum that in turn caused cell death of hematopoietic stem cells. Furthermore, UFBP1 deficiency diminished expression of key transcription factors essential for red blood cell development. Taken together, our study provides strong genetic evidence for the essential role of UFBP1 as well as other components of the Ufm1 system in hematopoietic development. Therefore, the ufmylation pathway may represent a novel therapeutic target in treatment of blood diseases.


Zdroje

1. Komatsu M, Chiba T, Tatsumi K, Iemura S, Tanida I, Okazaki N, et al. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. The EMBO journal 2004, 23(9): 1977–1986. 15071506

2. Tatsumi K, Sou YS, Tada N, Nakamura E, Iemura S, Natsume T, et al. A novel type of E3 ligase for the Ufm1 conjugation system. The Journal of biological chemistry 2010, 285(8): 5417–5427. doi: 10.1074/jbc.M109.036814 20018847

3. Daniel J, Liebau E. The ufm1 cascade. Cells 2014, 3(2): 627–638. doi: 10.3390/cells3020627 24921187

4. Tatsumi K, Yamamoto-Mukai H, Shimizu R, Waguri S, Sou YS, Sakamoto A, et al. The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. Nat Commun 2011, 2: 181. doi: 10.1038/ncomms1182 21304510

5. Neziri D, Ilhan A, Maj M, Majdic O, Baumgartner-Parzer S, Cohen G, et al. Cloning and molecular characterization of Dashurin encoded by C20orf116, a PCI-domain containing protein. Biochim Biophys Acta 2010, 1800(4): 430–438. doi: 10.1016/j.bbagen.2009.12.004 20036718

6. Wu J, Lei G, Mei M, Tang Y, Li H. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling. The Journal of biological chemistry 2010, 285(20): 15126–15136. doi: 10.1074/jbc.M110.110619 20228063

7. Lemaire K, Moura RF, Granvik M, Igoillo-Esteve M, Hohmeier HE, Hendrickx N, et al. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS One 2011, 6(4): e18517. doi: 10.1371/journal.pone.0018517 21494687

8. Yoo HM, Kang SH, Kim JY, Lee JE, Seong MW, Lee SW, et al. Modification of ASC1 by UFM1 is crucial for ERalpha transactivation and breast cancer development. Molecular cell 2014, 56(2): 261–274. doi: 10.1016/j.molcel.2014.08.007 25219498

9. Zhang M, Zhu X, Zhang Y, Cai Y, Chen J, Sivaprakasam S, et al. RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell death and differentiation 2015 (Epub ahead of print).

10. Pronk CJ, Rossi DJ, Mansson R, Attema JL, Norddahl GL, Chan CK, et al. Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell stem cell 2007, 1(4): 428–442. doi: 10.1016/j.stem.2007.07.005 18371379

11. Hu X, Pang Q, Shen Q, Liu H, He J, Wang J, et al. Ubiquitin-fold modifier 1 inhibits apoptosis by suppressing the endoplasmic reticulum stress response in Raw264.7 cells. International journal of molecular medicine 2014, 33(6): 1539–1546. doi: 10.3892/ijmm.2014.1728 24714921

12. Kwon J, Cho HJ, Han SH, No JG, Kwon JY, Kim H. A novel LZAP-binding protein, NLBP, inhibits cell invasion. The Journal of biological chemistry 2010, 285(16): 12232–12240. doi: 10.1074/jbc.M109.065920 20164180

13. Liu D, Wang WD, Melville DB, Cha YI, Yin Z, Issaeva N, et al. Tumor suppressor Lzap regulates cell cycle progression, doming, and zebrafish epiboly. Dev Dyn 2011, 240(6): 1613–1625. doi: 10.1002/dvdy.22644 21523853

14. Tanaka Y, Kurosaki M, Nishida N, Sugiyama M, Matsuura K, Sakamoto N, et al. Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C. Hum Mol Genet 2011, 20(17): 3507–3516. doi: 10.1093/hmg/ddr249 21659334

15. van Galen P, Kreso A, Mbong N, Kent DG, Fitzmaurice T, Chambers JE, et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature 2014, 510(7504): 268–272. doi: 10.1038/nature13228 24776803

16. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature reviews Molecular cell biology 2012, 13(2): 89–102. doi: 10.1038/nrm3270 22251901

17. Miharada K, Sigurdsson V, Karlsson S. Dppa5 improves hematopoietic stem cell activity by reducing endoplasmic reticulum stress. Cell reports 2014, 7(5): 1381–1392. doi: 10.1016/j.celrep.2014.04.056 24882002

18. Lee JW, Choi HS, Gyuris J, Brent R, Moore DD. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol 1995, 9(2): 243–254. 7776974

19. Jung DJ, Sung HS, Goo YW, Lee HM, Park OK, Jung SY, et al. Novel transcription coactivator complex containing activating signal cointegrator 1. Molecular and cellular biology 2002, 22(14): 5203–5211. 12077347

20. Bauer A, Mikulits W, Lagger G, Stengl G, Brosch G, Beug H. The thyroid hormone receptor functions as a ligand-operated developmental switch between proliferation and differentiation of erythroid progenitors. The EMBO journal 1998, 17(15): 4291–4303. 9687498

21. Angelin-Duclos C, Domenget C, Kolbus A, Beug H, Jurdic P, Samarut J. Thyroid hormone T3 acting through the thyroid hormone alpha receptor is necessary for implementation of erythropoiesis in the neonatal spleen environment in the mouse. Development 2005, 132(5): 925–934. 15673575

22. Kendrick TS, Payne CJ, Epis MR, Schneider JR, Leedman PJ, Klinken SP, et al. Erythroid defects in TRalpha-/- mice. Blood 2008, 111(6): 3245–3248. doi: 10.1182/blood-2007-07-101105 18203951

23. Bauer A, Tronche F, Wessely O, Kellendonk C, Reichardt HM, Steinlein P, et al. The glucocorticoid receptor is required for stress erythropoiesis. Genes & development 1999, 13(22): 2996–3002.

24. Evans T. Regulation of hematopoiesis by retinoid signaling. Experimental hematology 2005, 33(9): 1055–1061. 16140154

25. Sanchez-Aguilera A, Arranz L, Martin-Perez D, Garcia-Garcia A, Stavropoulou V, Kubovcakova L, et al. Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis. Cell stem cell 2014, 15(6): 791–804. doi: 10.1016/j.stem.2014.11.002 25479752

26. Zhang Y, Zhang M, Wu J, Lei G, Li H. Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS One 2012, 7(11): e48587. doi: 10.1371/journal.pone.0048587 23152784

27. Zhu X, Wang Y, Pi W, Liu H, Wickrema A, Tuan D. NF-Y recruits both transcription activator and repressor to modulate tissue- and developmental stage-specific expression of human gamma-globin gene. PLoS One 2012, 7(10): e47175. doi: 10.1371/journal.pone.0047175 23071749

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