I��B Is a Substrate for a Selective Pathway of Lysosomal Proteolysis

In lysosomes isolated from rat liver and spleen, a percentage of the intracellular inhibitor of the nuclear factor κ B (I��B) can be detected in the lysosomal matrix where it is rapidly degraded. Levels of I��B are significantly higher in a lysosomal subpopulation that is active in the direct uptake of specific cytosolic proteins. I��B is directly transported into isolated lysosomes in a process that requires binding of I��B to the heat shock protein of 73 kDa (hsc73), the cytosolic molecular chaperone involved in this pathway, and to the lysosomal glycoprotein of 96 kDa (lgp96), the receptor protein in the lysosomal membrane. Other substrates for this degradation pathway competitively inhibit I��B uptake by lysosomes. Ubiquitination and phosphorylation of I��B are not required for its targeting to lysosomes. The lysosomal degradation of I��B is activated under conditions of nutrient deprivation. Thus, the half-life of a long-lived pool of I��B is 4.4 d in serum-supplemented Chinese hamster ovary cells but only 0.9 d in serum-deprived Chinese hamster ovary cells. This increase in I��B degradation can be completely blocked by lysosomal inhibitors. In Chinese hamster ovary cells exhibiting an increased activity of the hsc73-mediated lysosomal degradation pathway due to overexpression of lamp2, the human form of lgp96, the degradation of I��B is increased. There are both short- and long-lived pools of I��B, and it is the long-lived pool that is subjected to the selective lysosomal degradation pathway. In the presence of antioxidants, the half-life of the long-lived pool of I��B is significantly increased. Thus, the production of intracellular reactive oxygen species during serum starvation may be one of the mechanisms mediating I��B degradation in lysosomes. This selective pathway of lysosomal degradation of I��B is physiologically important since prolonged serum deprivation results in an increase in the nuclear activity of nuclear factor κ B. In addition, the response of nuclear factor κ B to several stimuli increases when this lysosomal pathway of proteolysis is activated.

CIKS, a connection to I��B kinase and stress-activated protein kinase

Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals invariably involves transcription factors of the NF-κB and AP-1/ATF families. Activation of NF-κB factors is thought to be mediated primarily via I��B kinases (IKK), whereas that of AP-1/ATF can be mediated by stress-activated protein kinases (SAPKs; also named Jun kinases or JNKs). IKKα and IKKβ are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-κB essential modulator)/IKKγ. The latter protein is essential for activation of the IKKs, but its mechanism of action is not known. Here we describe the molecular cloning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protein that directly interacts with NEMO/IKKγ in cells. When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-κB-dependent reporter. Activation of NF-κB is prevented in the presence of kinase-deficient, interfering mutants of the IKKs. CIKS may help to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS could coordinate the activation of two stress-induced signaling pathways, functions reminiscent of those noted for tumor necrosis factor receptor-associated factor adaptor proteins.

Activation of NF-κB by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK–IKKα/β–I��B�� and MKK3/6–p38 MAP kinase signaling pathways in epithelial cells

Nontypeable Hemophilus influenzae (NTHi) is an important human pathogen in both children and adults. In children, it causes otitis media, the most common childhood infection and the leading cause of conductive hearing loss in the United States. In adults, it causes lower respiratory tract infections in the setting of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. The molecular mechanisms underlying the pathogenesis of NTHi-induced infections remain undefined, but they may involve activation of NF-κB, a transcriptional activator of multiple host defense genes involved in immune and inflammatory responses. Here, we show that NTHi strongly activates NF-κB in human epithelial cells via two distinct signaling pathways, NF-κB translocation-dependent and -independent pathways. The NF-κB translocation-dependent pathway involves activation of NF-κB inducing kinase (NIK)–IKKα/β complex leading to I��B�� phosphorylation and degradation, whereas the NF-κB translocation-independent pathway involves activation of MKK3/6–p38 mitogen-activated protein (MAP) kinase pathway. Bifurcation of NTHi-induced NIK–IKKα/β-I��B�� and MKK3/6–p38 MAP kinase pathways may occur at transforming growth factor-β activated kinase 1 (TAK1). Furthermore, we show that toll-like receptor 2 (TLR2) is required for NTHi-induced NF-κB activation. In addition, several key inflammatory mediators including IL-1β, IL-8, and tumor necrosis factor-α are up-regulated by NTHi. Finally, P6, a 16-kDa lipoprotein highly conserved in the outer membrane of all NTHi and H. influenzae type b strains, appears to also activate NF-κB via similar signaling pathways. Taken together, our results demonstrate that NTHi activates NF-κB via TLR2–TAK1-dependent NIK–IKKα/β-I��B�� and MKK3/6–p38 MAP kinase signaling pathways. These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases.

Khulāṣah-ʼi aḥvāl-i B��nū Bagum mukhāṭab ba-Mumtāz Maḥall : manuscript, undated

Biography of Banū Begam, surnamed Mumtāz Maḥall, and known as Tāj B��b��, wife of Shāh Jahān, and of the buildings connected with her name.

Kitāb Mufīd al-ḥi���āb : manuscript, 1910

Written surface: 9.5 x 18.8 cm, 25 lines per page, in clear naskhi script in black ink, on beige paper, with headings, keywords, and markings in red. Text: folios: 1b – 36a

Die durchführung der reformation in der ehemaligen freien reichsstadt, Weissenburg i.B.

"Verzeichnis der wiederholt angeführten archivalien und bücher": p. [vii]-viii.

Random number generation on the I.B.M. 360.

"Errata" ([3] p.) inserted.

I.B.A. of A. bulletin.

List of "Blue sky" laws is included in v. 1, no. 1; Brief of "Blue sky" laws in v. 1, no. 3; additional information in subsequent numbers.

al-Qism al-awwal[al-th⁻alith] min Kit⁻ab Nafḥ al-ṭibb min ghuṣn al-Andalus al-raṭi��b : wa-dhikr waz⁻irih⁻a lis⁻an al-d⁻in Ibn al-Khaṭ⁻ib /

Issued in parts. Comprises the first half of the work only.

Kriticheskai���a︡ literatura o proizvedenii︠a︡kh A.N. Ostrovskago : s portretom i b��ograficheskim ocherkom /

vyp. 1. 1852-1859 gg. -- vyp. 2. 1860-1867 gg. -- vyp. 3. 1868-1873 gg.

Kitāb-i Nuqṭat al-kāf : dar tārīkh-i ẓuhūr-i B��b va vaqāyi��-i hasht sāl-i avval az tārīkh-i B��b��yah /

Includes index.