Retinoic acid-induced protein ISGylation is dependent on interferon signal transduction.
Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier that forms conjugates with target protein substrates. As its name suggests, its expression and conjugation to other proteins are highly regulated by interferon (IFN). It was recently demonstrated that ISG15 expression, ISG15 conjugation, and several enzymes involved in ISG15 modification are upregulated in an acute promyelocytic cell line following treatment with retinoic acid, suggesting a possible retinoic acid induced IFN-independent ISG15 modification pathway. In this study, we examined a possible link between IFN signaling and retinoic acid-induced ISG15 conjugation. We observed that ISGylation can be induced by retinoic acid in two myeloid leukemia cell lines. By sandwich ELISA, we detected increased IFN secretion into cell culture media following retinoic acid treatment. Blockade of the type I IFN receptor with a neutralizing antibody blocked retinoic acid induced ISG15 expression and ISG15 conjugation. Taken together, these data suggested that retinoic acid-induced secretion of IFN plays a fundamental role in retinoic acid promoted ISGylation.
Dao
Chinh T
CT
Department of Molecular and Experimental Medicine, MEM-L51, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Luo
Jiann-Kae
JK
Zhang
Dong-Er
DE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D020298:U937 Cells; D014452:Ubiquitins / Q000378:metabolism*
D000970:Antineoplastic Agents; D016207:Cytokines; D016898:Interferon-alpha; D014452:Ubiquitins; D014212:Tretinoin; C074034:ISG15 protein, human