Roles in Health and Disease

Humans

In humans, many of the known moonlighting proteins function in cellular processes that can go wrong in cancer, diabetes, and other common diseases or are important in disease treatment, for example: DNA synthesis or repair; chromatin and cytoskeleton structure; angiogenesis; amino acid, protein, sugar, and lipid metabolic pathways; and as growth factors or cytokines (reviewed in Jeffery 2003a, b). Phosphoglucose isomerase/autocrine motility factor/neuroleukin in glycolysis and thymidine phosphorylase/platelet-derived endothelial cell growth factor (PDGF) in dTMP biosynthesis via the salvage pathway are two cytosolic enzymes that function as growth factors outside the cell (Gurney et al. 1986a, b; Chaput et al. 1988; Faik et al. 1988; Watanabe et al. 1991, 1996; Furukawa 1992; Xu et al. 1996). Phosphoglycerate kinase is another glycolytic enzyme that has a second role when secreted. Outside the cell it is a disulfide bond reductase that reduces plasmin, which enables the cleavage of plasmin to produce an angiogenesis inhibitor, angiostatin (Lay et al. 2000). Human thymosin beta-4 sulfoxide inhibits actin polymerization in the cytoplasm by sequestering G-actin (monomeric actin) (Safer et al. 1997). It is secreted in response to glucocorticoids and serves as an immunomodulatory signal to limit inflammation due to cell injury (Young et al. 1999).

Histone H1, which plays a structural role in chromatin fibers and is also involved in regulation of gene expression, has another function as a cell-surface receptor for thyroglobulin, which helps in the production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) (Brix et al. 1998). SMC-3 (stuctural maintenance of chromosome 3) is part of a complex that maintains proper sister chromatid cohesion throughout the cell cycle and during mitosis to ensure accurate chromosome segregation (Darwiche et al. 1999; Wu and Yu 2012). It is also a component of the Engelbreth-Holm-Swarm tumor matrix, the renal mesangial matrix, and the basement membrane of other tissues and is involved in the control of cell growth and transformation (Couchman et al. 1996; Ghiselli et al.

  • 1999) . Human Hsp60 is a mitochondrial heat-shock protein that aids in protein import into the mitochondria, correct protein folding, and the prevention of protein misfolding. It can also be displayed on the cell surface where it serves as a receptor for HDL by binding to the apolipoprotein apoA-II (Bocharov et al.
  • 2000) . The folate receptor alpha (FRalpha) is a GPI-anchored protein on the cell surface that is important for binding folate and its derivatives and bringing them into the cell through endocytosis, where it can play a role in preventing neural tube defects during embryogenesis and help prevent other diseases in adults. It was also recently found to be a transcription factor in the nucleus where it binds to the cis-regulatory elements of the promoter regions of the Fgfr4 and Hes1 genes to regulate their expression (Boshnjaku et al. 2012).

As the number of known moonlighting proteins increases, it is becoming clear that many also have key roles related to cellular complexity and coordinating cellular activities; these are important in systems biology and also discussed further in Chapter 4. Because of their dual functions and ability to switch between functions, a moonlighting protein can help the cell to respond to changing conditions in its environment or to changes in concentrations of metabolites within a cell as a feedback mechanism, or to help coordinate the actions of proteins with similar or complementary functions. The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that also regulates other channels (Stutts et al. 1995), including the outwardly rectifying chloride channel (ORCC) and a sodium channel (ENaC). In this way, moonlighting proteins can contribute to cellular homeostasis. They can also promote homeostasis throughout the organism because some moonlighting proteins are also involved in communication between different cell types within an organism.

Some of these moonlighting proteins are the focus of a great deal of study because one or more of their functions plays a key role in disease. As described above, a functioning CFTR protein that is properly targeted to the plasma membrane helps promote epithelial cell ion homeostasis through its actions as a chloride channel and regulator of other channels. Mutations in the CFTR result in the genetic disease cystic fibrosis, and alleviating all the symptoms of the disease will require re-acquisition of the multiple functions of the protein. In cancer, the moonlighting protein PGI/AMF has been found to be involved in breast cancer metastasis because it can affect tumor cell motility, but it can also cause differentiation of some leukemia cell lines. The P-glycoprotein is a transmembrane flip- pase that exports hydrophobic substances from the cell and also helps regulate volume-activated ion channels in response to cell swelling (Hardy et al. 1995). It can become a serious problem in cancer treatment, especially when it becomes overexpressed in cancer cells, because it can also export anti-cancer drugs, resulting in multidrug resistance and a decrease in effectiveness of chemotherapy.

For these human moonlighting proteins, especially those that might be potential therapeutic targets, understanding all their functions is important in alleviating disease as well as avoiding toxicity and side effects.

 
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