JNK has been suggested to be proapoptotic, antiapoptotic, or have no role in apoptosis depending on the cell type and stimulus used. The precise mechanism of JNK action, under conditions when it promotes cell survival, is not entirely clear. Here, we report that JNK is required for IL-3-mediated cell survival through phosphorylation and inactivation of the proapoptotic Bcl-2 family protein BAD. IL-3 withdrawal-induced apoptosis is promoted by inhibition of JNK but suppressed by expression of a constitutively active JNK. JNK phosphorylates BAD at threonine 201, thereby inhibiting BAD association with the antiapoptotic molecule BCL-X(L). IL-3 induces BAD phosphorylation at threonine 201, and replacement of threonine 201 by alanine generates a BAD mutant, which promotes IL-3 withdrawal-induced apoptosis. Thus, our results provide a molecular mechanism by which JNK contributes to cell survival.

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Summary The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The pro-survival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here we report that inactivation of the BH3-only protein BAD by IKK independently of NF-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ−/− mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel, due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26-phosphorylation promotes BAD pro-apoptotic activity, thereby accelerating TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the pro-apoptotic BH3-only BAD protein.

Autophagy is essential for maintaining tissue homeostasis. Although adaptors have been demonstrated to facilitate the assembly of the Atg14L-Beclin 1-Vps34-Vps15 complex, which functions in autophagosome formation, it remains unknown whether the autophagy machinery actively recruits such adaptors. WD40-repeat proteins are a large, highly conserved family of adaptors implicated in various cellular activities. However, the role of WD40-repeat-only proteins, such as RACK1, in postnatal mammalian physiology remains unknown. Here, we report that hepatocyte-specific RACK1 deficiency leads to lipid accumulation in the liver, accompanied by impaired Atg14L-linked Vps34 activity and autophagy. Further exploration indicates that RACK1 participates in the formation of autophagosome biogenesis complex upon its phosphorylation by AMPK at Thr50. Thr50 phosphorylation of RACK1 enhances its direct binding to Vps15, Atg14L, and Beclin 1, thereby promoting the assembly of the autophagy-initiation complex. These observations provide insight into autophagy induction and establish a pivotal role for RACK1 in postnatal mammalian physiology.

The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-Iinteracting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48-linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I-triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity.RIG-I | E3 ligase | RNF122 | innate immunity | type I interferon

Silica-supported Ni 3 P, Ni 12 P 5 , and Ni 2 P catalysts were prepared by the temperature-programmed reduction method from nickel phosphate precursors. A Ni/SiO 2 catalyst was also prepared as a reference. The effect of the initial Ni/P molar ratio in the precursor on the catalyst structure and hydrodechlorination performance was investigated. The physicochemical properties of the catalysts were characterized by means of N 2 adsorption, hydrogen temperature-programmed reduction, X-ray diffraction, X-ray photoelectron spectroscopy, ultraviolet and visible spectroscopy, hydrogen temperature-programmed desorption, and inductively coupled plasma spectroscopy. The catalyst activities in the hydrodechlorination of chlorobenzene were evaluated in a fixedbed reactor at atmospheric pressure. The silica-supported nickel phosphides exhibited superior hydrodechlorination activities to that of supported nickel. This can be attributed to the special physicochemical properties of nickel phosphides and a great amount of spillover hydrogen species. In nickel phosphides, there is a small amount of electron transfer from Ni to P, leading to a small positive charge on Ni. This favors a weakening of the interaction between chlorine and nickel sites, as well as between adsorbed hydrogen species and nickel phosphides. The "ensemble effect" of P is also beneficial in decreasing the coverage of chlorine on nickel sites. Because of the reduced interaction between adsorbed hydrogen species and nickel phosphides, the energy barrier of the hydrogen spillover on the silica-supported nickel phosphide catalysts decreases, which accounts for the increased amount of spillover hydrogen species on the catalyst surface. Spillover hydrogen species not only promote the hydrogenolysis of the C-Cl bond, but also favor the removal of chlorine ions from the surface of the catalysts. Hydrodechlorination over the nickel phosphide catalysts is characterized by a reaction induction period that becomes longer with increasing phosphorus content in the catalyst precursor. This is related to the blocking of active sites by excess phosphorus.