Ube1L and Protein ISGylation Are Not Essential for Alpha/Beta Interferon Signaling

Abstract

The expression of ubiquitin-like modifier ISG15 and its conjugation to target proteins are highly induced by interferon (IFN) stimulation and during viral and bacterial infections. However, the biological significance of this modification has not been clearly understood. To investigate the function of protein modification by ISG15, we generated a mouse model deficient in UBE1L, an ISG15-activating enzyme. Ube1L^−/− mice did not produce ISG15 conjugates but expressed free ISG15 normally. ISGylation has been implicated in the reproduction and innate immunity. However, Ube1L^−/− mice were fertile and exhibited normal antiviral responses against vesicular stomatitis virus and lymphocytic choriomeningitis virus infection. Our results indicate that UBE1L and protein ISGylation are not critical for IFN-α/β signaling via JAK/STAT activation. Moreover, using Ube1L/Ubp43 double-deficient mice, we showed that lack of UBP43, but not the increase of protein ISGylation, is related to the increased IFN signaling in Ubp43-deficient mice.

We thank members of the laboratory of D.-E. Zhang for valuable discussions.

This work was supported by National Institutes of Health grants CA079849 and GM066955 (D.-E.Z.). J.-K.L. was partially supported by the Leukemia Research Foundation. W.Z. is a Leukemia and Lymphoma Society fellow. The Stein Endowment Fund has partially supported the Department of Molecular and Experimental Medicine departmental molecular biology service laboratory for DNA sequencing and oligonucleotide synthesis.

This report is paper 17626-MEM from The Scripps Research Institute.