The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

Summary: Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5) and RIG-I, are crucial for host recognition of non-self RNAs, especially viral RNA. Thus, the expression and activation of RLRs play fundamental roles in eliminating the invading RNA viruses and maintaining immune homeostasis. However, how RLR expression is tightly regulated remains to be further investigated. In this study, we identified a major histocompatibility complex (MHC)-encoded gene, tripartite interaction motif 40 (TRIM40), as a suppressor of RLR signaling by directly targeting MDA5 and RIG-I. TRIM40 binds to MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination via its E3 ligase activity, leading to their proteasomal degradation. TRIM40 deficiency enhances RLR-triggered signaling. Consequently, TRIM40 deficiency greatly enhances antiviral immune responses and decreases viral replication in vivo. Thus, we demonstrate that TRIM40 limits RLR-triggered innate activation, suggesting TRIM40 as a potential therapeutic target for the control of viral infection. : Optimal activation of RLR-triggered innate immune response is crucial for the elimination of invading RNA viruses and maintenance of immune homeostasis. Zhao et al. show that tripartite interaction motif 40 (TRIM40) promotes proteasomal degradation of both RIG-I and MDA5 through K27- and K48-linked ubiquitination to attenuate innate antiviral immune responses. Keywords: TRIM40, MDA5, RIG-I, innate immunity, type I interfero

Effect of diets enriched in n-6 or n-3 fatty acid on dry matter intake, energy balance, oxidative stress, and milk fat profile of transition cows

The objective of this study was to determine the effect of dietary supplementation of n-3 polyunsaturated fatty acids (PUFA) and n-6 PUFA on dry matter intake (DMI), energy balance, oxidative stress, and performance of transition cows. Forty-five multiparous Holstein dairy cows with similar parity, body weight (BW), body condition score (BCS), and milk yield were used in a completely randomized design during a 56-d experimental period including 28 d prepartum and 28 d postpartum. At 240 d of pregnancy, cows were randomly assigned to one of the 3 isoenergetic and isoprotein dietary treatments, including a control ration containing 1% hydrogenated fatty acid (CON), a ration with 8% extruded soybean (HN6, high n-6 PUFA source), and a ration with 3.5% extruded flaxseed (HN3; high n-3 PUFA source). The HN6 and HN3 diets had an n-6/n-3 ratio of 3.05:1 and 0.64:1 in prepartum cows and 8.16:1 and 1.59:1 in postpartum cows, respectively. During the prepartum period (3, 2, and 1 wk before calving), DMI, DMI per unit of BW, total net energy intake, and net energy balance were higher in the HN3 than in the CON and NH6 groups. During the postpartum period (2, 3, and 4 wk after calving), cows fed HN3 and HN6 diets both showed increasing DMI, DMI as a percentage of BW, and total net energy intake compared with those fed the CON diet. The BW of calves in the HN3 group was 12.91% higher than those in the CON group. Yield and nutrient composition of colostrum (first milking after calving) were not affected by HN6 or HN3 but milk yield from 1 to 4 wk of milking was significantly improved compared with CON. During the transition period, BW, BCS, and BCS changes were not affected. Cows fed the HN6 diet had a higher plasma NEFA concentration compared with the CON cows during the prepartum period. Feeding HN3 reduced the proportion of de novo fatty acids and increased the proportion of preformed long-chain fatty acids in regular milk. In addition, the n-3 PUFA-enriched diet reduced the n-6/n-3 PUFA ratio in milk. In conclusion, increasing the n-3 fatty acids concentration in the diet increased both DMI during the transition period and milk production after calving, and supplementing n-3 fatty acids was more effective in mitigating the net energy balance after calving.ISSN:0022-0302ISSN:1525-319

Pseudouridine synthase 1 regulates erythropoiesis via transfer RNAs pseudouridylation and cytoplasmic translation

Summary: Pseudouridylation plays a regulatory role in various physiological and pathological processes. A prime example is the mitochondrial myopathy, lactic acidosis, and sideroblastic anemia syndrome (MLASA), characterized by defective pseudouridylation resulting from genetic mutations in pseudouridine synthase 1 (PUS1). However, the roles and mechanisms of pseudouridylation in normal erythropoiesis and MLASA-related anemia remain elusive. We established a mouse model carrying a point mutation (R110W) in the enzymatic domain of PUS1, mimicking the common mutation in human MLASA. Pus1-mutant mice exhibited anemia at 4 weeks old. Impaired mitochondrial oxidative phosphorylation was also observed in mutant erythroblasts. Mechanistically, mutant erythroblasts showed defective pseudouridylation of targeted tRNAs, altered tRNA profiles, decreased translation efficiency of ribosomal protein genes, and reduced globin synthesis, culminating in ineffective erythropoiesis. Our study thus provided direct evidence that pseudouridylation participates in erythropoiesis in vivo. We demonstrated the critical role of pseudouridylation in regulating tRNA homeostasis, cytoplasmic translation, and erythropoiesis

Table 1S.docx

The information on cows was not included in the statistical analysis</p