Dataset Information

Usp25-Erlin1/2 activity limits cholesterol flux to trigger TLR3 responses and restrict a broad range of viruses

ABSTRACT: Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations are regulated, particularly during virus infections are poorly understood. Our previous screen to identify cellular deubiquitylases activated during influenza virus infection revealed Usp25 as a prominent hit. Here we show that Usp25-deleted cells display >10-fold increase in pathogenic influenza virus and SARS-CoV-2 production, which were rescued upon reconstitution with the wild-type, but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25 -/- or Usp25 C178S cells, activating Srebp2, with concomitant increase in cholesterol efflux, LC3+ and Rab11+ compartments, and attenuated TLR3-dependent responses. In contrast, depletion of Smurf1, an E3 ligase, triggered Usp25 degradation and rescued this effect. Smurf1-deficient cells were refractory to infection by various pathogenic viruses, (e.g. SARS-CoV-2, H5N1 and H7N9) and induced robust Type I interferon response. Our study therefore defines the function of a deubiquitylase that serves to restrict a broad range of viruses by reprogramming lipid biosynthetic flux to install appropriate inflammatory responses.

INSTRUMENT(S):

ORGANISM(S): Influenza A Virus Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Influenza

SUBMITTER: Sumana Sanyal

LAB HEAD: Sumana Sanyal

PROVIDER: PXD034797 | Pride | 2026-02-09

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	2020-12-22-decoys-contam-UP000005640_reviewed_yes_UP000132424_20201222.FASTA	Fasta
	20201203_Flag25_Mock_1_Slot1-32_1_1427.d.zip	Other
	20201203_Flag25_Mock_1_Slot1-32_1_1427.pepXML	Pepxml
	20201203_Flag25_Mock_2_Slot1-33_1_1433.d.zip	Other
	20201203_Flag25_Mock_2_Slot1-33_1_1433.pepXML	Pepxml

Items per page:

1 - 5 of 28

Publications

Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.

Teo Qi Wen QW Wong Ho Him HH Heunis Tiaan T Stancheva Viktoriya V Hachim Asmaa A Lv Huibin H Siu Lewis L Ho Julian J Lan Yun Y Mok Chris Ka Pun CKP Ulferts Rachel R Sanyal Sumana S

Developmental cell 20230907 22

Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild ...[more]

PMID: 37683630

Similar Datasets

Project description:We previously reported widespread differential expression of long non-protein-coding RNAs (ncRNAs) in response to virus infection. Here, we expanded the study through small RNA transcriptome sequencing analysis of the host response to both severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza virus infections across four founder mouse strains of the Collaborative Cross, a recombinant inbred mouse resource for mapping complex traits. We observed differential expression of over 200 small RNAs of diverse classes during infection. A majority of identified microRNAs (miRNAs) showed divergent changes in expression across mouse strains with respect to SARS-CoV and influenza virus infections and responded differently to a highly pathogenic reconstructed 1918 virus compared to a minimally pathogenic seasonal influenza virus isolate. Novel insights into miRNA expression changes, including the association with pathogenic outcomes and large differences between in vivo and in vitro experimental systems, were further elucidated by a survey of selected miRNAs across diverse virus infections. The small RNAs identified also included many non-miRNA small RNAs, such as small nucleolar RNAs (snoRNAs), in addition to nonannotated small RNAs. An integrative sequencing analysis of both small RNAs and long transcripts from the same samples showed that the results revealing differential expression of miRNAs during infection were largely due to transcriptional regulation and that the predicted miRNA-mRNA network could modulate global host responses to virus infection in a combinatorial fashion. These findings represent the first integrated sequencing analysis of the response of host small RNAs to virus infection and show that small RNAs are an integrated component of complex networks involved in regulating the host response to infection. IMPORTANCE: Most studies examining the host transcriptional response to infection focus only on protein-coding genes. However, mammalian genomes transcribe many short and long non-protein-coding RNAs (ncRNAs). With the advent of deepsequencing technologies, systematic transcriptome analysis of the host response, including analysis of ncRNAs of different sizes, is now possible. Using this approach, we recently discovered widespread differential expression of host long (>200 nucleotide[nt]) ncRNAs in response to virus infection. Here, the samples described in the previous report were again used, but we sequenced another fraction of the transcriptome to study very short (about 20 to 30 nt) ncRNAs. We demonstrated that virus infection also altered expression of many short ncRNAs of diverse classes. Putting the results of the two studies together, we show that small RNAs may also play an important role in regulating the host response to virus infection. The small RNA transcriptome deep sequencing analysis was performed on lung samples from our previously published study (Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling , X Peng, MBio. 2010 Oct 26;1(5). pii: e00206-10.). We infected four of the eight founder mouse strains used in generating the Collaborative Cross, a recombinant inbred mouse resource for mapping complex traits (41). These strains included 129S1/SvImJ (129/S1), WSB/EiJ (WSB), PWK/PhJ (PWK), and CAST/EiJ (CAST) mice. Ten-week-old mice were intranasally infected with phosphate-buffered saline (PBS) alone or with 1X10^5 PFU of mouse adapted severe acute respiratory syndrome coronavirus (SARS-CoV; rMA15), or 500 PFU of influenza A virus strain A/Pr/8/34 (H1N1; PR8). To match the previous whole-transcriptome analysis, we performed small RNA transcriptome sequencing analysis on the same eight samples from mice with SARS-CoV infections, including one SARS-CoV rMA15-infected mouse and one matched mock-infected mouse from each of the four strains at 2 days postinfection (dpi). In addition, we sequenced the small RNA transcriptome for 12 samples obtained from influenza virus infected mice, including two PR8-infected mice and one matched mockinfected mouse from each of the four strains at 2 dpi.