ISG15 modulates development of the erythroid lineage.
Activation of erythropoietin receptor allows erythroblasts to generate erythrocytes. In a search for genes that are up-regulated during this differentiation process, we have identified ISG15 as being induced during late erythroid differentiation. ISG15 belongs to the ubiquitin-like protein family and is covalently linked to target proteins by the enzymes of the ISGylation machinery. Using both in vivo and in vitro differentiating erythroblasts, we show that expression of ISG15 as well as the ISGylation process related enzymes Ube1L, UbcM8 and Herc6 are induced during erythroid differentiation. Loss of ISG15 in mice results in decreased number of BFU-E/CFU-E in bone marrow, concomitant with an increased number of these cells in the spleen of these animals. ISG15(-/-) bone marrow and spleen-derived erythroblasts show a less differentiated phenotype both in vivo and in vitro, and over-expression of ISG15 in erythroblasts is found to facilitate erythroid differentiation. Furthermore, we have shown that important players of erythroid development, such as STAT5, Globin, PLC γ and ERK2 are ISGylated in erythroid cells. This establishes a new role for ISG15, besides its well-characterized anti-viral functions, during erythroid differentiation.
Centre National de la Recherche Scientifique UMR3306, Orsay, France.
Ana Leticia
AL
Maragno
Martine
M
Pironin
Hélène
H
Alcalde
Xiuli
X
Cong
Klaus-Peter
KP
Knobeloch
Frederic
F
Tangy
Dong-Er
DE
Zhang
Jacques
J
Ghysdael
Christine Tran
CT
Quang
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000172:deficiency / Q000378:metabolism*; D004900:Erythroblasts / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism; D005914:Globins / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000172:deficiency / Q000378:metabolism
D016207:Cytokines; C489550:G1p2 protein, mouse; D050799:STAT5 Transcription Factor; D014452:Ubiquitins; D004921:Erythropoietin; D005914:Globins; D007372:Interferons; D019950:Mitogen-Activated Protein Kinase 1; D051966:Phospholipase C gamma