Selenoproteins: The Answers Behind Seleniums' Profound Mechanisms of Action

In recent years, significant progress has been made that explains the functions and physiological roles of human selenoproteins. These two studies show that newly discovered research identifying new selenoprotein families and new functions assigned to previously characterized selenoproteins. The research has provided insights into the mechanisms by which Sec is synthesized and incorporated into proteins. Above all, it is clear that “selenoproteins do not simply function as antioxidant enzymes.” Be sure to scroll down to the bottom of the page for the full text study that describes a number of new findings on the importance of selenoproteins.

Here is what you will learn in these two studies:

1. The micronutrient selenium (Se) is known to regulate immune functions via selenoproteins.

2. Selenoproteins may inhibit autophagy, which limits the availability of nutrients to bacteria, thus reducing the risk of acute infections. The nutrients in selenoproteins affect the outcome of an infection by influencing host immune response, and reveal potential novel targets for antibacterial therapies.

3. The functional characterization of selenoproteins and analyses of selenoproteomes may explain the various biological and biomedical effects of Se and help identify new molecular pathways and biological processes that are dependent on selenoproteins.

4. Selenoproteins might serve as potential targets for the development of new therapies for a number of different diseases that are known to be affected by dietary Se and/or altered organismal Se status, including cancer, diabetes, viral infection, inflammation, AIDS, as well as neurodegenerative and cardiovascular diseases.

STUDY 1: MACROPHAGE SELENOPROTEINS RESTRICT INTRACELLULAR REPLICATION OF FRANCISELLA TULARENSIS

Published in Journal of Immunology

ABSTRACT

There has been a growing appreciation for the influence of dietary nutrients on the microbiome as well as host response to infectious disease. The micronutrient selenium (Se) is known to regulate immune functions via selenoproteins, a class of proteins that contain the 21st amino acid selenocysteine. However, the mechanisms by which selenoproteins regulate immune functions during an acute infection are not clear. Therefore, we investigated the role of macrophage (Mac) selenoproteins during an acute bacterial infection.

Francisella tularensis (Ft.), the causative agent of tularemia, is a gram-negative intracellular bacterium. Since Ft. infects and replicates primarily in Macs, we measured the bacterial replication in Macs derived from TrspM mice that are unable to synthesize selenoproteins. TrspM Macs had uncontrolled replication of Ft. compared to wild-type (WT) Macs. Moreover, TrspM mice were more susceptible to Ft. infection and harbored significantly higher levels of bacteria in their livers and spleens as compared to WT mice, which suggests that Mac selenoproteins are essential for restricting bacterial replication and promoting host survival. Since Ft. replication is closely associated with autophagy, we investigated if the Mac selenoproteins had an effect on autophagy.

In fact, our data indicates that selenoproteins inhibit autophagy, which may limit the availability of nutrients to the bacteria. Future studies will seek to establish the influence of selenoproteins on the microbiome and how these changes impact the infectious disease process. Our studies demonstrate that nutrients affect the outcome of an infection by influencing host immune response, and reveal potential novel targets for antibacterial therapies.

Source: R L. Markley et al. Macrophage selenoproteins restrict intracellular replication of Francisella tularensis

STUDY 2: SELENOPROTEINS: MOLECULAR PATHWAYS AND PHYSIOLOGICAL ROLES

Published in Physiological Reviews

ABSTRACT

Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions.

Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. SEE FIGURE 1. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

cypress-selenoproteins.jpg

The genetic code illustrating the dual function of the UGA condon and that Sec is the 21st amino acid that is encoded by UGA

 

Summary excerpt from full text study (link at the bottom of the page)

  1. Although most of the well-characterized selenoproteins perform redox functions, which require the unique chemical properties of Sec, it has now become clear that selenoproteins do not simply function as antioxidant enzymes.
  2. The specific functions of selenoproteins involve thiol-based redox signaling, control of the reduced state of Cys residues in cytosolic and mitochondrial proteins, removal of hydrogen peroxide, repair of oxidatively damaged proteins, control of cytoskeleton/actin assembly, formation and quality control of structural disulfide bonds in proteins, hormone activation and inactivation, selenoprotein synthesis, Se transport, protein folding and ER-associated degradation, and other functions.
  3. The important role of micronutrient Se in human health and development is likely mediated by the combined action of selenoproteins constituting the human selenoproteome. As such, selenoproteins might serve as potential targets for the development of new therapies for a number of different diseases that are known to be affected by dietary Se and/or altered organismal Se status, including cancer, diabetes, viral infection, inflammation, AIDS, as well as neurodegenerative and cardiovascular diseases.

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