Although transcriptional induction of stress
Although transcriptional induction of stress genes constitutes a major cellular defense program against a variety of stressors, posttranslational control directly regulating the activities of preexisting stress proteins provides a faster-acting alternative response . In fact, to add functional diversity and adaption to their alternative environments, proteins may respond to stresses by a transformation of structure and, then, function . The rapid and transient nature of many PTMs allows efficient signal transmission in response to internal and environmental stimuli. On the other hand, the excess of reactive chemical species may be able to post-translationally modify proteins, resulting in the disturbance of cellular redox systems and the incidence of oxidative stress. For instance, cysteine oxidation in KRN 7000 inhibitor is an emerging class of redox protein PTMs that creates a range of modifications, which can regulate signal transduction and biological functions [97,98].
PTMs in MeHg-induced neurotoxicity
Conclusions and perspectives MeHg exposure continues to remain an environmental health burden due to its toxic effects, especially on the brain. Population whose diet consists largely of fish is at the greatest risk for exposure. The developing fetus and children are susceptible to its neurotoxic effects. Studies on the molecular mechanism of MeHg-neurotoxicity are pivotal to our understanding of its toxic effects and the development of preventive measures. MeHg is a soft electrophile that has extremely high affinity for nucleophilic thiol (SH) and selenol (SeH) groups, thus a large pool of cellular molecules could be its candidate targets. PTMs, such phosphorylation, ubiquitination, and acetylation, are essential mechanisms in the biosynthesis of proteins and play pivotal role in the regulation of cellular environment. MeHg modulates the activities of MAPKs (ERK1/2, JNK, p38MAPK), PKA and PKC, which are important in modulating pathways related to its neurotoxicity, such as cellular redox status, cell differentiation, and cell death. Mitochondrial damage and increased ROS generation caused by MeHg are important steps in the process of PTMs of proteins that mark MeHg neurotoxicity. Nfr2 is important in combating oxidative stress, and many pathways have been proved to be involved in MeHg-induced activation of Nrf2. Accumulated data shows that antioxidant proteins (such as GPxs and TrxR) are likely to be modulated by MeHg via a PTMs mechanism. Although researches on MeHg-neurotoxicity have illustrated many important aspects of its mechanism, such as oxidative stress, calcium dyshomeostasis, and disrupted glutamine recycling, etc., we still lack knowledge on the molecular events triggered by MeHg. For example, cells contain more than 19,000 SH containing proteins and 25 selenoproteins, however, we do not know with which of these proteins MeHg directly interacts. The PTMs modification can be a result of direct inhibition of the proteins by MeHg or can be indirect either inhibition or activation via modulation of up-stream thiol- or selenol-containing proteins. Since PTMs is a conserved and essential process for maintaining cellular homeostasis and function, and many newly defined cellular machineries are carried out by proteins that are modified by multiple PTMs mechanisms, current investigations should offer new insight on the relation between PTMs and MeHg neurotoxicity.
Conflicts of interest
Acknowledgments This work was supported by the National Institutes of Health to MA [grant numbers NIEHS R01ES007331, NIEHS R01ES010563 and NIEHS R01ES020852]. The authors also would like to thank Ms Priscila B. Rosa for the help with the graphic illustrations.