The regulatory-targeting subunit (R GL , also called G M ) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/R GL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of R GL . To investigate the function of the phosphatase, R GL knockout mice were generated. Animals lacking R GL show no obvious defects. The R GL protein is absent from the skeletal and cardiac muscle of null mutants and present at ϳ50% of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by ϳ50% in the R GL -deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant R GL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by ϳ90%. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and R GL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that R GL is genetically linked to glycogen metabolism, since its loss decreases PP1 and basal GS activities and glycogen accumulation. However, PP1G/R GL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.In recent years, the generality that the activity of the type 1 serine/threonine protein phosphatases (PP1) is dictated by the associated noncatalytic subunits has emerged. These ancillary proteins are thought to target the catalytic component (C1) to distinct subcellular locales in proximity to substrates, to confer specificity, and to regulate activity (10,21,33,41). To date, more than 30 C1-binding polypeptides have been identified that direct the enzyme to a variety of subcellular structures, including glycogen (6,24,25,49,59,60), myosin (2), ribosomes (31), nuclei (4, 13), and neuronal structures (5). A subset of C1-binding proteins includes inhibitory proteins such as inhibitors 1 and 2 (48, 67) and DARPP-32 (46). Four C1-glycogen-targeting subunits are presently known. R GL , also called G M , was the first glycogen-binding subunit of PP1 identified (59), and the corresponding holoenzyme, PP1G/ R GL , consists of the 124-kDa R GL protein (60) in association with C1. R GL is exclusively expressed in skeletal and cardiac muscle (37, 60). The NH 2 -terminal 240 amino acids contain binding sites for glycogen and C1 (64), whereas a hydrophobic region between residues 1063 and 1097 in the COOH terminus anchors the protein to membrane (45,60). Of the other three glycoge...

The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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Most adults are infected with Epstein-Barr virus (EBV), a virus that establishes a lifelong latent infection in B lymphocytes and is associated with a variety of cancers. In normal individuals, latent infection with EBV typically poses no health risk, but upon immunosuppression, either following organ transplantation or HIV infection, malignancies and lymphoproliferative diseases can result. We have utilized both transgenic mice and EBV transformed lymphoblastoid cell lines (LCLs) as models of EBV latent infection to explore the function of latent membrane protein 2A (LMP2A) of EBV. This has allowed us to identify important functional domains of LMP2A, essential host proteins necessary for LMP2A function, and the effect of LMP2A on normal B cell function. These studies have provided a more complete understanding of the role of LMP2A in EBV latency and tumorigenesis and may allow for the identification of novel therapeutics for the treatment or eradication of EBV latent infections and associated proliferative disorders.

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