Ubp43 regulates BCR-ABL leukemogenesis via the type 1 interferon receptor signaling

Abstract

Interferon (IFN) signaling induces the expression of interferon-responsive genes and leads to the activation of pathways that are involved in the innate immune response. Ubp43 is an ISG15-specific isopeptidase, the expression of which is activated by IFN. Ubp43 knock-out mice are hypersensitive to IFN-␣/␤ and have enhanced resistance to lethal viral and bacterial infections. Here we show that in addition to protection against foreign pathogens, Ubp43 deficiency increases the resistance to oncogenic transformation by BCR-ABL. BCR-ABL viral transduction/transplantation of wild-type bone marrow cells results in the rapid development of a chronic myeloid leukemia (CML)-like myeloproliferative disease; in contrast, a significantly increased latency of disease development is observed following BCR-ABL viral transduction/transplantation of Ubp43-deficient bone marrow cells. 4,5 These kinases then phosphorylate STAT1 and STAT2, leading to the activation of downstream signal transduction pathways. 6-9 Furthermore, a family of suppressors of cytokine signaling (SOCS) and several protein tyrosine phosphatases negatively regulate the STAT signaling pathway. [10][11][12] Defects in such regulators may result either in the loss of response or a hyperresponse to IFN stimulation.Type 1 IFN signaling triggers the expression of hundreds of IFN-stimulated genes (ISGs). 13,14 Among these is the ISG15 deconjugating enzyme Ubp43 (Usp18). [15][16][17][18][19] ISG15 is a ubiquitinlike modifier whose expression and conjugation to other proteins (ISGylation) is strongly increased upon type 1 IFN stimulation. 20,21 Ubp43-deficient cells accumulate higher levels of ISGylated proteins and are hypersensitive to type 1 IFN treatment, as evidenced by the enhanced and prolonged activation of STAT phosphorylation in these cells. 22,23 Furthermore, Ubp43 knock-out mice show a higher resistance to viral and bacterial infection, 24,25 indicating an important role for Ubp43 in the regulation of IFN signal transduction. Recently, using cells with different levels of protein ISGylation and Ubp43 expression, we demonstrated that UBP43 is a novel negative regulator of type 1 interferon signaling and this function is independent of Ubp43 isopeptidase activity against ISG15 conjugates. 26,27 Type 1 IFNs suppress cell proliferation and promote apoptosis, 28 as such they have been used in the clinical treatment of several cancers, including leukemia. 29 A specific example is in the treatment of chronic myeloid leukemia (CML), where IFN was the primary choice before imatinib mesylate became available. [30][31][32] In nearly all cases of CML, patients carry a reciprocal translocation between chromosomes 9 and 22. 33,34 This results in a fusion protein consisting of the N-terminal portion of BCR joined to most of the ABL tyrosine kinase. The chimeric BCR-ABL tyrosine kinase is constitutively activated as a result of the oligomerization domain provided by BCR. The tyrosine kinase activity of BCR-ABL activates several signaling intermediates, such as Ras, Akt, ...

Suppression of Interferon (IFN)-inducible Genes and IFN-mediated Functional Responses in BCR-ABL-expressing Cells

“…This was shown by studies demonstrating that, in contrast to wild-type BCR-ABL, a kinasedefective mutant did not suppress formation of Stat complexes and IFN-dependent gene transcription. An interesting possibility is that suppression of Isg15 expression by BCR-ABL may lead to a positive feedback loop leading to suppression of Stat phosphorylation, since ISGylation has been previously linked to the regulation of Stat1 phosphorylation (73), whereas cells lack- ing the ISG15-specific isopeptidase, Ubp43, are more resistant to oncogenic transformation by BCR-ABL (74). However, the validity of such a hypothesis remains to be determined in future studies.…”

Identification of Host Genes Linked with the Survivability of Chickens Infected with Recombinant Viruses Possessing H5N1 Surface Antigens from a Highly Pathogenic Avian Influenza Virus

“…USP18, which negatively regulates the innate immune response against viral infections, was shown to be involved in such host genes (27). Studies on USP18-deficient mice showed that increasing the immunoactivity of ISG15 made the mice resistant against viral and bacterial infections (28,41,51), yet the mechanism of USP18 induction in infected hosts is controversial. One possible mechanism is a negative-feedback reaction against overexpression of the ISG15 gene, accompanied by a protective response after viral infection.…”

Identification of USP18 as an Important Regulator of the Susceptibility to IFN-α and Drug-Induced Apoptosis

“…Within this respect, it has been recently shown that, in a mouse model, USP18/Ubp43 absence improves the resistance to oncogenic transformation by BCR-ABL. This resistance to leukemic development is dependent on type I IFN signaling (36).…”