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Innate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can better escape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by which transcriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouse lungs, and patient PBMCs, we showed that genes on the complementary strand (“trans” genes) influenced by TRT were involved in the disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishment increased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 induced TRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT by reducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138−/− mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.

Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent. However, the lack of a clear understanding of the indications of metformin limits its efficacy. Here, we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment (T18) compared to those of the untreated cells at day 0 (T0) yielded candidate genes. Knockdown of a group of cyclin-dependent kinases (CDKs), including CDK1, CDK4, and CDK6, confirmed the results of the screen. Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo. Although cell cycle parameters were not further altered under the combination treatment, investigation of the metabolome revealed significant changes in cell metabolism, especially with regard to fatty acid oxidation, the tricarboxylic acid cycle and aspartate metabolism. Such changes appeared to be mediated through inhibition of the mTOR pathway. Collectively, our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.

We functionally characterized RhoS/RSA-14-44 as a new member of Rho GTPase subfamily in spermatogenesis, which provides a direct link between Rho family GTPase and the proteasome biogenesis., Most Rho family GTPases serve as key molecular switches in a wide spectrum of biological processes. An increasing number of studies have expanded their roles to the spermatogenesis. Several members of Rho family have been confirmed to be essential for mammalian spermatogenesis, but the precise roles of this family in male reproduction have not been well studied yet. Here we report a surprising function of an atypical and testis-specific Rho GTPase, RSA-14-44 in spermatogenesis. Featured by unique structural and expressional patterns, RSA-14-44 is distinguished from three canonical members of Rho cluster. Thus, we define RSA-14-44 as a new member of Rho GTPases family and rename it RhoS (Rho in spermatogenic cells). RhoS associates with PSMB5, a catalytic subunit of the proteasome, in a series of stage-specific spermatogenic cells. More importantly, RhoS does not directly modulate the cellular proteasome activity, but participates in regulating the stability of “unincorporated” PSMB5 precursors. Meanwhile, our data demonstrate that the activation of RhoS is prerequisite for negatively regulating the stability of PSMB5 precursors. Therefore, our finding uncovers a direct and functional connection between the Rho GTPase family and the pathway of proteasome biogenesis and provide new clues for deciphering the secrets of spermatogenesis.

Rhomboid proteins perform a wide range of important functions in a variety of organisms. Recent studies have revealed that rhomboid proteins are involved in human cancer progression; however, the underlying molecular mechanism remains largely unclear. Here we show that RHBDD1, a rhomboid intramembrane serine protease, is highly expressed and closely associated with survival in patients with colorectal cancer. We observe that inactivation of RHBDD1 decreases tumor cell growth. Further studies show that RHBDD1 interacts with proTGFα and induces the ADAM-independent cleavage and secretion of proTGFα. The secreted TGFα further triggers the activation of the EGFR/Raf/MEK/ERK signalling pathway. Finally, the positive correlation of RHBDD1 expression with the EGFR/Raf/MEK/ERK signalling pathway is further corroborated in a murine model of colitis-associated colorectal cancer. These findings provide evidence of a growth-promoting role for RHBDD1 in colorectal cancer and may aid the development of tumor biomarkers or antitumor therapeutics., Rhomboid proteins are involved in human cancer progression. Here, the authors show that RHBDD1, a rhomboid intramembrane serine protease, promotes tumor growth in colorectal cancer via cleavage and secretion of TGFα, and activation of the EGFR/Raf/MEK/ERK signalling pathway.

The ankyrin repeat domain 49 (ANKRD49) is an evolutionarily conserved protein highly expressed in testes. However, the function of ANKRD49 in spermatogenesis is unknown. In this study, we found that ANKRD49 resides primarily in nucleus of spermatogonia, spermatocytes and round spermatids. ANKRD49 overexpression augments starvation-induced autophagy in male germ GC-1 cells whereas shRNA knockdown of ANKRD49 attenuates the autophagy. Inhibition of NF-κB pathway by its inhibitors or p65 siRNA prevents the ANKRD49-dependent autophagy augmentation, demonstrating that ANKRD49 enhances autophagy via NF-κB pathway. Our findings suggest that ANKRD49 plays an important role in spermatogenesis via promotion of autophagy-dependent survival.

Spermatogenesis is an extremely intricate process that is tightly regulated and orchestrated by a series of well-coordinated gene expression programmes. Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine kinase that functions in a wide variety of developmental events. Nevertheless, the function of NLK in spermatogenesis has not been investigated. In this study, we found that the distribution of NLK in mice exhibited a dynamic change during testicular development and gradually became concentrated in the acrosomes of elongated spermatids. NLK overexpression promoted etoposide-induced apoptosis of male germ cell-derived GC-1 cells, while knockdown of NLK by RNA interference (RNAi) attenuated etoposide-induced apoptosis. Our findings suggest that NLK plays an important role in etoposide-induced germ cell apoptosis and may be associated with spermatogenesis.