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1.  IL-17-committed Vγ4+ γδ T cell deficiency in a spontaneous Sox13 mutant CD45.1 congenic mouse substrain protects from dermatitis 
Nature immunology  2013;14(6):10.1038/ni.2585.
IL-17-committed γδ T (γδT17) cells participate in many immune responses but their developmental requirements and subset specific functions remain poorly understood. Here we report that a commonly used CD45.1+ congenic C57BL/6 mouse substrain is characterized by a selective deficiency in Vγ4+ γδT17 cells. This trait is due to a spontaneous mutation in the transcription factor Sox13 that causes an intrinsic defect in development of these cells in the neonatal thymus. γδT17 cells migrate at low rates from skin to lymph nodes. In a model of psoriasis-like dermatitis, Vγ4+ γδT17 cells expand markedly in lymph nodes and home to inflamed skin. Sox13 mutant mice are protected from psoriasis-like skin changes, identifying a role for Sox13-dependent γδT17 cells in this inflammatory condition.
PMCID: PMC3660499  PMID: 23624556
2.  Evidence for Mycobacteria in Sarcoidosis 
Despite its recognition as a distinct granulomatous disease for over a century, the etiology of sarcoidosis remains to be defined. Since the early 1900s, infectious agents have been suspected in causing sarcoidosis. For much of this time, mycobacteria were considered a likely culprit, yet until recently, the supporting evidence has been tenuous at best. In this review, we evaluate the reported association between mycobacteria and sarcoidosis. Historically, mycobacterial infection has been investigated using histologic stains, cultures of lesional tissue or blood, and identification of bacterial nucleic acids or bacterial antigens. More recently, advances in biochemical, molecular, and immunological methods have produced a more rigorous analysis of the antigenic drivers of sarcoidosis. The result of these efforts indicates that mycobacterial products likely play a role in at least a subset of sarcoidosis cases. This information, coupled with a better understanding of genetic susceptibility to this complex disease, has therapeutic implications.
PMCID: PMC3361363  PMID: 21659662
sarcoidosis; mycobacteria; granulomas; microorganisms; peptides; immune response
3.  Mitotic Raptor Promotes mTORC1 Activity, G2/M Cell Cycle Progression, and Internal Ribosome Entry Site-Mediated mRNA Translation▿ †  
Molecular and Cellular Biology  2010;30(13):3151-3164.
The mTOR signaling complex integrates signals from growth factors and nutrient availability to control cell growth and proliferation, in part through effects on the protein-synthetic machinery. Protein synthesis rates fluctuate throughout the cell cycle but diminish significantly during the G2/M transition. The fate of the mTOR complex and its role in coordinating cell growth and proliferation signals with protein synthesis during mitosis remain unknown. Here we demonstrate that the mTOR complex 1 (mTORC1) pathway, which stimulates protein synthesis, is actually hyperactive during mitosis despite decreased protein synthesis and reduced activity of mTORC1 upstream activators. We describe previously unknown G2/M-specific phosphorylation of a component of mTORC1, the protein raptor, and demonstrate that mitotic raptor phosphorylation alters mTORC1 function during mitosis. Phosphopeptide mapping and mutational analysis demonstrate that mitotic phosphorylation of raptor facilitates cell cycle transit through G2/M. Phosphorylation-deficient mutants of raptor cause cells to delay in G2/M, whereas depletion of raptor causes cells to accumulate in G1. We identify cyclin-dependent kinase 1 (cdk1 [cdc2]) and glycogen synthase kinase 3 (GSK3) pathways as two probable mitosis-regulated protein kinase pathways involved in mitosis-specific raptor phosphorylation and altered mTORC1 activity. In addition, mitotic raptor promotes translation by internal ribosome entry sites (IRES) on mRNA during mitosis and is demonstrated to be associated with rapamycin resistance. These data suggest that this pathway may play a role in increased IRES-dependent mRNA translation during mitosis and in rapamycin insensitivity.
PMCID: PMC2897579  PMID: 20439490
4.  eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy 
The Journal of Cell Biology  2008;181(2):293-307.
Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.
PMCID: PMC2315676  PMID: 18426977

Results 1-4 (4)