Mycobacterium tuberculosis sigL encodes an extracytoplasmic function (ECF) sigma factor and is adjacent to a gene for a membrane protein (Rv0736) that contains a conserved HXXXCXXC sequence. This motif is found in anti-sigma factors that regulate several ECF sigma factors, including those that control oxidative stress responses. In this work, SigL and Rv0736 were found to be cotranscribed, and the intracellular domain of Rv0736 was shown to interact specifically with SigL, suggesting that Rv0736 may encode an anti-sigma factor of SigL. An M. tuberculosis sigL mutant was not more susceptible than the parental strain to several oxidative and nitrosative stresses, and sigL expression was not increased in response to these stresses. In vivo, sigL is expressed from a weak SigL-independent promoter and also from a second SigL-dependent promoter. To identify SigL-regulated genes, sigL was overexpressed and microarray analysis of global transcription was performed. Four small operons, sigL (Rv0735)-Rv0736, mpt53 (Rv2878c)-Rv2877c, pks10 (Rv1660)-pks7 (Rv1661), and Rv1139c-Rv1138c, were among the most highly upregulated genes in the sigL-overexpressing strain. SigL-dependent transcription start sites of these operons were mapped, and the consensus promoter sequences TGAACC in the ؊35 region and CGTgtc in the ؊10 region were identified. In vitro, purified SigL specifically initiated transcription from the promoters of sigL, mpt53, and pks10. Additional genes, including four PE_PGRS genes, appear to be regulated indirectly by SigL. In an in vivo murine infection model, the sigL mutant strain showed marked attenuation, indicating that the sigL regulon is important in M. tuberculosis pathogenesis.The Mycobacterium tuberculosis genome encodes 13 sigma factors, of which 10 fall into the extracytoplasmic function (ECF) subfamily. Three of these sigma factor genes are located 5Ј of genes that encode proteins containing an HXXXCXXC motif, which is found in several anti-sigma factors, including Streptomyces coelicolor RsrA (2,15,17,25), Rhodobacter sphaeroides ChrR (23), and M. tuberculosis RshA (35). For both S. coelicolor SigR-RsrA and M. tuberculosis SigH-RshA, it has been demonstrated that this motif in the anti-sigma protein is a key element of a redox switch that affects the interaction between sigma and anti-sigma and thus regulates sigma factor activity in response to intracellular oxidative stress (24, 35). In the case of RsrA and ChrR, this cysteine-rich motif has been shown to bind zinc, and it has been suggested that this is a general property of this motif, leading to the term zinc-associated anti-sigma factor (ZAS) (17,23,24).In addition to sigH, the other M. tuberculosis sigma factor genes linked to these putative ZAS protein genes are sigE and sigL. SigE, like SigH, has been shown to be a key regulator of the mycobacterial response to oxidative and heat stresses (21, 37). In addition, M. tuberculosis SigB, though it is not linked to a similar putative anti-sigma factor gene, is regulated by SigE and SigH and has be...

Mycobacterial SigE and SigH both initiate transcription from the sigB promoter, suggesting that they recognize similar sequences. Through mutational and primer extension analyses, we determined that SigE and SigH recognize nearly identical promoters, with differences at the 3′ end of the −35 element distinguishing between SigE- and SigH-dependent promoters.

The gamma-aminobutyric acid receptor type B 1 (GABA(B) R1) is located approximately at 200 kb telomeric to HLA-A on chromosome 6. It has 11 single-nucleotide polymorphisms (SNPs). We studied the most common of its SNPs (T1974C) in a panel of 118 normal Caucasians from New England and 161 epileptic patients of Caucasian ancestry residing in USA. The frequency of the polymorphism did not differ between patients and controls. Here, we report that the allele C of this SNP in the GABA(B) R1 gene is in linkage disequilibrium with HLA-A11 (P<0.00001) and to a lesser extent with HLA-A1 (P<0.01).