Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway.
IFN-stimulatory gene factor 15 (ISG15) is a ubiquitin-like protein, which is conjugated to many cellular proteins. However, its role in protein degradation is unclear. Here, we show that ISG15 is highly elevated and extensively conjugated to cellular proteins in many tumors and tumor cell lines. The increased levels of ISG15 in tumor cells were found to be associated with decreased levels of polyubiquitinated proteins. Specific knockdown of ISG15 expression using ISG15-specific small interfering RNA (siRNA) was shown to increase the levels of polyubiquitinated proteins, suggesting an antagonistic role of ISG15 in regulating ubiquitin-mediated protein turnover. Moreover, siRNA-mediated down-regulation of the major E2 for ISG15 (UbcH8), which blocked the formation of ISG15 protein conjugates, also increased the levels of polyubiquitinated proteins. Together, our results suggest that the ISG15 pathway, which is deregulated during tumorigenesis, negatively regulates the ubiquitin/proteasome pathway by interfering with protein polyubiquitination/degradation.
Desai
Shyamal D
SD
Department of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Haas
Arthur L
AL
Wood
Laurence M
LM
Tsai
Yu-Chen
YC
Pestka
Sidney
S
Rubin
Eric H
EH
Saleem
Ahamed
A
Nur-E-Kamal
Alam
A
Liu
Leroy F
LF
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D014452:Ubiquitins / Q000096:biosynthesis / Q000502:physiology; D015854:Up-Regulation
D016207:Cytokines; D011506:Proteins; D034741:RNA, Small Interfering; D025801:Ubiquitin; D014452:Ubiquitins; C074034:ISG15 protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease