The Role of Ubiquitin System in Autophagy

Autophagy is a highly conserved lysosomal degradation pathway, which has been shown to play a pivotal role during normal physiological and pathological conditions. Many proteins and signaling pathways have been shown to regulate autophagy during different stages of the process. Modifying autophagy-related proteins (Atg) by posttranslational modification (PTM) is an important way to control proper autophagic activity. Ubiquitination is one of the PTM that has a crucial role in controlling protein stability and functions. Proteins can be conjugated with ubiquitin chains with different topologies that are associated with different outcomes. Many autophagy regulators are found to be substrates for ubiquitin E3 ligases or deubiquitinating enzymes (DUBs). Ubiquitination modifications of these autophagy regulators result in autophagy induction or termination. Moreover, ubiquitin is also involved in selective autophagy by acting as a degradation signal. Here, we are going to review how E3 ligases and DUBs function in autophagy regulation and discuss the recent findings about ubiquitination regulation in autophagy-related processes and diseases

Rho-kinase regulates tissue morphogenesis via non-muscle myosin and LIM-kinase during Drosophila development

BACKGROUND: The Rho-kinases (ROCKs) are major effector targets of the activated Rho GTPase that have been implicated in many of the Rho-mediated effects on cell shape and movement via their ability to affect acto-myosin contractility. The role of ROCKs in cell shape change and motility suggests a potentially important role for Rho-ROCK signaling in tissue morphogenesis during development. Indeed, in Drosophila, a single ROCK ortholog, DRok, has been identified and has been found to be required for establishing planar cell polarity. RESULTS: We have examined a potential role for DRok in additional aspects of tissue morphogenesis using an activated form of the protein in transgenic flies. Our findings demonstrate that DRok activity can influence multiple morphogenetic processes, including eye and wing development. Furthermore, genetic studies reveal that Drok interacts with multiple downstream effectors of the Rho GTPase signaling pathway, including non-muscle myosin heavy chain, adducin, and Diaphanous in those developmental processes. Finally, in overexpression studies, we determined that Drok and Drosophila Lim-kinase interact in the developing nervous system. CONCLUSION: These findings indicate widespread diverse roles for DRok in tissue morphogenesis during Drosophila development, in which multiple DRok substrates appear to be required

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs during Pneumocystis pneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs from Pneumocystis-infected mice compared to those incubated with Gr-1+ cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1+ cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP

Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia

The combination of all-trans retinoic acid (ATRA) and primaquine (PMQ) has been shown to be effective for therapy of Pneumocystis pneumonia (PCP). Since a high concentration of ATRA has significant adverse effects, the possibility that vitamin D can be used to replace ATRA for PCP therapy was investigated. C57BL/6 mice were immunosuppressed by depleting CD4+ cells and infected with Pneumocystis murina 1 week after initiation of immunosuppression. Three weeks after infection, the mice were treated orally for 3 weeks with vitamin D3 (VitD3) alone, PMQ alone, a combination of VitD3 and PMQ (VitD3-PMQ), or a combination of trimethoprim and sulfamethoxazole (TMP-SMX). Results showed that VitD3 (300 IU/kg/day) had a synergistic effect with PMQ (5 mg/kg/day) for therapy of PCP. Flow cytometric studies showed that this VitD3-PMQ combination recovered the CD11blow CD11chigh alveolar macrophage population in mice with PCP as effectively as TMP-SMX. The VitD3-PMQ combination also reduced the massive infiltration of inflammatory cells into the lungs and the severity of lung damage. VitD3 was also shown to reduce the dose of TMP-SMX required for effective treatment of PCP. Taken together, results of this study suggest that a VitD3-PMQ combination can be used as an alternative therapy for PCP

Individual Subjective Initiative Merge Model Based on Cellular Automaton

The merge control models proposed for work zones are classified into two types (Hard Control Merge (HCM) model and Soft Control Merge (SCM) model) according to their own control intensity and are compared with a new model, called Individual Subjective Initiative Merge (ISIM) model, which is based on the linear lane-changing probability strategy in the merging area. The attention of this paper is paid to the positive impact of the individual subjective initiative for the whole traffic system. Three models (ISIM, HCM, and SCM) are established and compared with each other by two order parameters, that is, system output and average vehicle travel time. Finally, numerical results show that both ISIM and SCM perform better than HCM. Compared with SCM, the output of ISIM is 20 vehicles per hour higher under the symmetric input condition and is more stable under the asymmetric input condition. Meanwhile, the average travel time of ISIM is 2000 time steps less under the oversaturated input condition