Isoleucine 44 Hydrophobic Patch Controls Toxicity of Unanchored, Linear Ubiquitin Chains through NF-κB Signaling

Cells

GustavoM. Silva¹  JessicaR. Blount²  Kozeta Libohova²  SokolV. Todi² 

[1] Department of Biology, Duke University, Durham, NC 27708, USA;Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield St., Scott Hall Rm. 3108, Detroit, MI 48201, USA;

关键词: Drosophila melanogaster;    innate immunity;    NF-κB signaling;    ubiquitination;    unanchored poly-ubiquitin;   

DOI  :  10.3390/cells9061519

来源: DOAJ

【 摘 要 】

Ubiquitination is a post-translational modification that regulates cellular processes by altering the interactions of proteins to which ubiquitin, a small protein adduct, is conjugated. Ubiquitination yields various products, including mono- and poly-ubiquitinated substrates, as well as unanchored poly-ubiquitin chains whose accumulation is considered toxic. We previously showed that transgenic, unanchored poly-ubiquitin is not problematic in Drosophila melanogaster. In the fruit fly, free chains exist in various lengths and topologies and are degraded by the proteasome; they are also conjugated onto other proteins as one unit, eliminating them from the free ubiquitin chain pool. Here, to further explore the notion of unanchored chain toxicity, we examined when free poly-ubiquitin might become problematic. We found that unanchored chains can be highly toxic if they resemble linear poly-ubiquitin that cannot be modified into other topologies. These species upregulate NF-κB signaling, and modulation of the levels of NF-κB components reduces toxicity. In additional studies, we show that toxicity from untethered, linear chains is regulated by isoleucine 44, which anchors a key interaction site for ubiquitin. We conclude that free ubiquitin chains can be toxic, but only in uncommon circumstances, such as when the ability of cells to modify and regulate them is markedly restricted.

【 授权许可】

Unknown