Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients.

In contrast to animal and fungal cells, green plant cells contain one or multiple chloroplasts, the organelle(s) in which photosynthetic reactions take place. Chloroplasts are believed to have originated from an endosymbiotic event and contain DNA that codes for some of their proteins. Most chloroplast proteins are encoded by the nuclear genome and imported with the help of sorting signals that are intrinsic parts of the polypeptides. Here, we show that a chloroplast-located protein in higher plants takes an alternative route through the secretory pathway, and becomes N-glycosylated before entering the chloroplast.

Nitrogenase harbors three distinct metal prosthetic groups that are required for its activity. The simplest one is a [4Fe-4S] cluster located at the Fe protein nitrogenase component. The MoFe protein component carries an [8Fe-7S] group called P-cluster and a [7Fe-9S-C-Mo-R-homocitrate] group called FeMo-co. Formation of nitrogenase metalloclusters requires the participation of the structural nitrogenase components and many accessory proteins, and occurs both in situ, for the P-cluster, and in external assembly sites for FeMo-co. The biosynthesis of FeMo-co is performed stepwise and involves molecular scaffolds, metallochaperones, radical chemistry, and novel and unique biosynthetic intermediates. This review provides a critical overview of discoveries on nitrogenase cofactor structure, function, and activity over the last four decades. CONTENTS 1. Introduction 4922 2. Structure of Mo−Nitrogenase Complex 4924 3. Organization of Mo−Nitrogenase Genes and Proposed Functions of Their Products 4925 3.1. Genomic Organization of A. vinelandii Mo− Nitrogenase Genes 4925 3.2. Proposed Functions of nif Gene Products 4926 3.3. Essential and Ancillary Proteins for Mo− Nitrogenase 4926 3.4. Biosynthesis of Genetically Simpler Mo− Nitrogenases 4927 4. Biosynthesis of Simple [Fe-S] Clusters for Nitrogenase: Roles of NifU and NifS 4928 4.1. Information from nif U and nif S Mutagenesis 4928 4.2. NifS Is a Cysteine Desulfurase Involved in Metallocluster Biosynthesis 4928 4.3. NifU Is a Molecular Scaffold for Assembly of Nitrogenase-Destined [4Fe-4S] Clusters 4929 4.4. NifS-Mediated Assembly of Transient [Fe-S] Clusters at NifU 4930 4.5. NifS and NifU Transfer of [4Fe-4S] Cluster to Fe Protein 4930 5. Fe Protein Maturation 4930 5.1. Role of NifM 4930 5.2. Proposed Function of NifM in Fe Protein Maturation 4931 6. Interaction of Maturation Factors with Cofactor Deficient MoFe Protein 4932 7. Formation of MoFe Protein P-Clusters 4933 7.1. NifU and NifS 7.2. Fe Protein Is Required for P-Cluster Formation 7.3. NifZ Is Involved in P-Cluster Formation 7.3.1. Model 1: NifZ Is Only Required for Maturation of Second P-Cluster in Each Apo-MoFe Protein Molecule 7.3.2. Model 2: NifZ Is Involved in Maturation of Both P-Clusters 8. FeMo-co: Description of the Cofactor and Methods to Measure Its Biosynthesis 8.1. Discovery and Isolation of FeMo-co 8.2. In Vitro Systems for FeMo-Cofactor Synthesis and Insertion 9. Model for FeMo-co Biosynthesis 10. Biosynthesis of FeMo-co Fe-S Core: Roles of NifU, NifS, NifB, and FdxN 10.1. NifS and NifU Assembly of Precursor [Fe-S] Clusters for FeMo-co 10.2. NifB and NifB-co 10.2.1. Information from nif B Mutagenesis 10.2.2. Identification and Isolation of NifB-co, the Product of NifB Activity 10.2.3. Interstitial Atom of FeMo-co Is Present at NifB-co