Stringent control of inflammasome signaling pathway is important for maintaining immunological balance, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. In this study, we found that the signaling pathway dependent on mitochondrial antiviral signaling protein (MAVS) was required for the optimal activation of apoptosis-associated specklike protein (ASC)–dependent inflammasome. In particular, TNFR-associated factor 3 was found to be a direct E3 ligase for ASC. Ubiquitination of ASC at Lys174 was critical for speck formation and inflammasome activation. Deficiency in MAVS or TNFR-associated factor 3 impaired ASC ubiquitination and cytosolic aggregates formation, resulting in reduced inflammasome response upon RNA virus infection. This study has identified a previously unrecognized role of MAVS in the regulation of inflammasome signaling and provided molecular insight into the mechanisms by which ubiquitination of ASC controls inflammasome activity through the formation of ASC specks.
Innate immunity to viruses involves receptors such as Retinoic Acid Induced Gene-1 (RIG-I), which senses viral RNA and triggers a signaling pathway involving the outer mitochondrial membrane protein mitochondrial antiviral signaling (MAVS). Recent work has identified that NLRX1, a member of another class of innate immune receptors, sequesters MAVS away from RIG-I and thereby prevents mitochondrial antiviral immunity. In this study, we demonstrate that the proteasome PSMA7 (α4) subunit associates with MAVS in vivo and in vitro. Expression of PSMA7 results in a potent inhibition of RIG-1 and MAVS-mediated IFN-β promoter activity; conversely, depletion of PSMA7 with small interference RNA enhances virus-induced type I IFN production, with consequent reduction of virus replication. Furthermore, a striking reduction in the abundance of endogenous MAVS with overexpressed PSMA7 was found and virus infection leads to transient increase in the endogenous PSMA7 protein level. Cumulatively, these results suggest that PSMA7 is a negative regulator of the MAVS-mediated innate immunity that probably serves to attenuate the establishment of an antiviral state during viral infection, highlighting the biological significance of PSMA7-MAVS association as an important cellular regulatory control.
Hash coding has been widely used in the approximate nearest neighbor search for large-scale image retrieval. Recently, many deep hashing methods have been proposed and shown largely improved performance over traditional featurelearning methods. Most of these methods examine the pairwise similarity on the semantic-level labels, where the pairwise similarity is generally defined in a hard-assignment way. That is, the pairwise similarity is '1' if they share no less than one class label and '0' if they do not share any. However, such similarity definition cannot reflect the similarity ranking for pairwise images that hold multiple labels. In this paper, an improved deep hashing method is proposed to enhance the ability of multi-label image retrieval. We introduce a pairwise quantified similarity calculated on the normalized semantic labels. Based on this, we divide the pairwise similarity into two situations -'hard similarity' and 'soft similarity', where cross-entropy loss and mean square error loss are adapted respectively for more robust feature learning and hash coding. Experiments on four popular datasets demonstrate that, the proposed method outperforms the competing methods and achieves the state-of-the-art performance in multi-label image retrieval.Index Terms-image retrieval, convolutional neural network, semantic label, pairwise similarity, deep hashing.
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