The findings of Qiu et al represent the first instance
The findings of Qiu et al. (2016) represent the first instance of a Ub-specific mono-ADP-ribosyltransferase, as well as the first documentation of E1/E2 independent ubiquitination. Post-translational modification of Ub certainly adds layers of complexity to our understanding of the Ub signal and should be taken into account for future investigations. Just as PINK1 phosphorylation of S65 in Ub dramatically alters Ub’s signaling properties, mono-ADP-ribosylation of R42 could also and should be further investigated. The cross-talk between Ub signaling pathways and ADP-ribosylation has just begun to be explored, and in one example assembly of 26S proteasome was enhanced by poly-ADP-ribosylated PI31 (Cho-Park and Steller, 2013). Tankyrase, the human poly-ADP-ribose polymerase that modifies PI31 also functions in Wnt/β-catenin signaling and maintenance of telomeres, but it is not clear how this directly affects Ub signaling (Smith and de Lange, 2000, Yang et al., 2016). In a more direct link, the E3 Ub ligase RNF146 uses a WWE domain to select poly-ADP-ribose modified proteins (BLZF1 and CASC3), which are subsequently ubiquitinated and degraded by the proteasome (Zhang et al., 2011).
Strictly in the context of mono-ADP-ribosylation and proteins containing the mART motif, many remain to be investigated in both pathogenic bacteria and humans. The presence of the mART motif in other members of the SidE IWR-1-endo family suggests that the function of SdeA is conserved. Furthermore, the importance of SdeA in invasion does make SdeA a therapeutic candidate, and Qiu et al. (2016) have laid the groundwork. With additional structural and functional characterization, this may be a possibility and provide a new means of intervention against deadly human pathogens. Clearly, L. pneumophila has a diverse arsenal of biochemical weapons capable of affecting numerous host pathways, often without a clear link to Ub.
Introduction Panax ginseng C.A. Mey (Arialaceae) has been used in health food and traditional herbal medicine for more than 1000years. It can prevent the risks of various cancers (Yun & Choi, 1995). It is known to be toxic (Chang, Seo, Gyllenhaal, & Block, 2003) but its effects on the cardiovascular, immune, renal, and central nervous systems are undefined (Gao et al., 2009, Gao et al., 2013, Wang et al., 2006, Xu et al., 2013). There is commercial interest in ginseng on the basis of its purported cancer prevention benefits (Wang et al., 2007, Yi et al., 2010). Ginsenosides from the plant genus Panax are a class of steroid glycosides and triterpene saponins. Ginsenosides and derivatives with less polar chemical structures possess higher cytotoxic activity towards cancer cells (Dong et al., 2011). Previous studies have demonstrated that Panax ginseng could prevent malignancy by inhibiting the 26S proteasome (Chang et al., 2008, Wong et al., 2010). However, there have been no studies on the effects of Panax ginseng on ubiquitin-activating enzyme (UAE or E1) in the ubiquitin activation of the ubiquitin–proteaosome system (UPP). The UPP broadly involves proteolysis in biochemical processes and is a potential target for cancer therapy. The UPP degrades unfolding or damaged proteins by an ATP-dependent mechanism (Ciechanover, Elias, Heller, Ferber, & Hershko, 1980). It also plays an important role in cell cycle regulation, DNA damage repair, and has implications for tumourigenesis (Tu et al., 2012). Ubiquitination is catalyzed by the sequential action of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin protein ligase (E3) (Hershko & Ciechanover, 1998). In humans, there is a single essential E1 and over 30 distinct E2s. E3s, of which there are estimated to be between 500 and 1000, are largely responsible for conferring specificity to ubiquitination (Ciechanover and Schwartz, 2004, Fang and Weissman, 2004). E1 is the common first step in ubiquitination, whether the proteasome represents the final destination of degradation for many ubiquitinated proteins.