The E3 ubiquitin ligase c-IAP1 regulates PCSK9-mediated LDLR degradation: Linking the TNF-α pathway to cholesterol uptake

Proprotein convertase subtilisin/kexin type 9 (PCSK9), in addition to LDLR (low-density lipoprotein receptor) and APOB (apolipoprotein B), is one of three loci implicated in autosomal dominant hypercholesterolaemia (ADH)^1^. A number of PCSK9 gain-of-function mutations and loss-of-function mutations have been identified from families afflicted with ADH with hypercholesterolaemia or hypocholesterolaemia, respectively^1-4^. In humans, the main function of PCSK9 appears to be the post-transcriptional regulation of the number of cell-surface LDL receptors^5-7^. To date, only LDLR and its closest family members VLDLR and ApoER2 have been shown to bind with PCSK9^8,9^. To find new binding partners for PCSK9, we used a shotgun proteomic method to analyse the protein complex pulled down by immunoprecipitation against FLAG-tagged PCSK9 protein. Among 22 potential novel binding proteins identified, we found that the cellular inhibitor of apoptosis protein 1 (c-IAP1^10^) and the TNF receptor-associated factor 2 (TRAF2^11^) complex are regulated differently in different dominant PCSK9 mutations that occur naturally. Further immunoprecipitation analysis showed that c-IAP1 is a direct binding partner for PCSK9. One of the "gain-of-function" mutants, PCSK9-S127R, which has impaired autocatalytic activity, is defective in binding to c-IAP1. The other dominant mutation, PCSK9-D374Y^12^, which is 10-fold more potent in degrading the LDLR protein than wild-type PCSK9, can be significantly ubiquitinated by c-IAP1 in vitro. The ubiquitinated PCSK9-D374Y is unable to degrade LDLR, which is its main cause of hypercholesterolaemia in patients. These results indicate that there is a novel cholesterol uptake regulation pathway linking PCSK9/LDLR to the E3 ubiquitin ligase c-IAP1 in a TNF-[alpha] response pathway. This highlights the possibility of developing new treatments for human cardiovascular diseases through ubiquitin ligase-mediated ubiquitination of target proteins in cholesterol metabolism

Unified Gas-kinetic Wave-Particle Methods III: Multiscale Photon Transport

In this paper, we extend the unified gas-kinetic wave-particle (UGKWP) method to the multiscale photon transport. In this method, the photon free streaming and scattering processes are treated in an un-splitting way. The duality descriptions, namely the simulation particle and distribution function, are utilized to describe the photon. By accurately recovering the governing equations of the unified gas-kinetic scheme (UGKS), the UGKWP preserves the multiscale dynamics of photon transport from optically thin to optically thick regime. In the optically thin regime, the UGKWP becomes a Monte Carlo type particle tracking method, while in the optically thick regime, the UGKWP becomes a diffusion equation solver. The local photon dynamics of the UGKWP, as well as the proportion of wave-described and particle-described photons are automatically adapted according to the numerical resolution and transport regime. Compared to the $S_n$ -type UGKS, the UGKWP requires less memory cost and does not suffer ray effect. Compared to the implicit Monte Carlo (IMC) method, the statistical noise of UGKWP is greatly reduced and computational efficiency is significantly improved in the optically thick regime. Several numerical examples covering all transport regimes from the optically thin to optically thick are computed to validate the accuracy and efficiency of the UGKWP method. In comparison to the $S_n$ -type UGKS and IMC method, the UGKWP method may have several-order-of-magnitude reduction in computational cost and memory requirement in solving some multsicale transport problems.Comment: 27 pages, 15 figures. arXiv admin note: text overlap with arXiv:1810.0598

TaylorAECNet: A Taylor Style Neural Network for Full-Band Echo Cancellation

This paper describes aecX team's entry to the ICASSP 2023 acoustic echo cancellation (AEC) challenge. Our system consists of an adaptive filter and a proposed full-band Taylor-style acoustic echo cancellation neural network (TaylorAECNet) as a post-filter. Specifically, we leverage the recent advances in Taylor expansion based decoupling-style interpretable speech enhancement and explore its feasibility in the AEC task. Our TaylorAECNet based approach achieves an overall mean opinion score (MOS) of 4.241, a word accuracy (WAcc) ratio of 0.767, and ranks 5th in the non-personalized track (track 1)

Overexpression of OsRAN2 in rice and Arabidopsis renders transgenic plants hypersensitive to salinity and osmotic stress

Nucleo-cytoplasmic partitioning of regulatory proteins is increasingly being recognized as a major control mechanism for the regulation of signalling in plants. Ras-related nuclear protein (Ran) GTPase is required for regulating transport of proteins and RNA across the nuclear envelope and also has roles in mitotic spindle assembly and nuclear envelope (NE) assembly. However, thus far little is known of any Ran functions in the signalling pathways in plants in response to changing environmental stimuli. The OsRAN2 gene, which has high homology (77% at the amino acid level) with its human counterpart, was isolated here. Subcellular localization results showed that OsRan2 is mainly localized in the nucleus, with some in the cytoplasm. Transcription of OsRAN2 was reduced by salt, osmotic, and exogenous abscisic acid (ABA) treatments, as determined by real-time PCR. Overexpression of OsRAN2 in rice resulted in enhanced sensitivity to salinity, osmotic stress, and ABA. Seedlings of transgenic Arabidopsis thaliana plants overexpressing OsRAN2 were overly sensitive to salinity stress and exogenous ABA treatment. Furthermore, three ABA- or stress-responsive genes, AtNCED3, AtPLC1, and AtMYB2, encoding a key enzyme in ABA synthesis, a phospholipase C homologue, and a putative transcriptional factor, respectively, were shown to have differentially induced expression under salinity and ABA treatments in transgenic and wild-type Arabidopsis plants. OsRAN2 overexpression in tobacco epidermal leaf cells disturbed the nuclear import of a maize (Zea mays L.) leaf colour transcription factor (Lc). In addition, gene-silenced rice plants generated via RNA interference (RNAi) displayed pleiotropic developmental abnormalities and were male sterile

Function of Brassica napus BnABI3 in Arabidopsis gs1, an Allele of AtABI3, in Seed Development and Stress Response

Abscisic acid (ABA) has been implicated in plant adaptation to various environmental stresses in addition to the regulation of seed dormancy and leaf senescence. ABI3 is a B3 domain-containing family protein and functions in the ABA signaling pathway during seed development. To date, the ABI3 orthologous have not been studied in Brassica napus. The aim of this study is to investigate the function of BnABI3 in plant development and stress response. Here, we identified an Arabidopsis line (gs1) from a population of mutagenized seeds and showed that GS1 is a new allele of AtABI3. When the Arabidopsis gs1 mutant was transformed with the BnABI3 gene, the transformed plants produced seeds that turned yellow and acquired desiccation tolerance. Moreover, BnABI3 regulates seed coat development and mucilage secretion by directly targeting the AtMUM1 and AtGATL5 genes. In addition, we showed that BnABI3 expression rescued gs1 freezing-induced green seed coloration by targeting AtSGR1/2 in transgenic Arabidopsis. BnABI3 is also involved in lateral root development and conferred a novel interaction between ABA and auxin signaling in roots. The potential role of ABI3 protein in endoplasmic reticulum homoeostasis was also tested. Altogether, our results indicated that BnABI3 mediates both plant development and the stress response