Nuclear translocation of the 4-pass transmembrane protein Tspan8

Huang, Yuwei; Li, Junjian; Du, Wanqing; Li, Siyang; Liu, Ying; Qu, Haozhi; Xv, Jingxuan; Yu, Li; Zhu, Rongxuan; Wang, Hongxia

doi:10.1038/s41422-021-00522-9

Cited by 14 publications

(19 citation statements)

References 11 publications

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“…7G). In addition, we found that VANGL2-TBK1 is located in the cytosol, although VANGL2 has four consecutive transmembrane domains, suggesting that the cytoplasmic location of VANGL2 is similar to some other well-studied transmembrane proteins, including Tspan8, PD-L1, IFITM3, and ACE2 (36)(37)(38)(39), and the underlying mechanism needs further investigation. Further in vivo studies found that mice with myeloid specific deletion of VANGL2 was beneficial to inhibit the replication of VSV due to stronger IFN-I responses, and these CKO mice were more resistant to lethal VSV Fig.…”

Section: Discussionmentioning

confidence: 83%

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Xie

et al. 2023

Sci. Adv.

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Stringent control of type I interferon (IFN-I) signaling is critical to potent innate immune responses against viral infection, yet the underlying molecular mechanisms are still elusive. Here, we found that Van Gogh–like 2 (VANGL2) acts as an IFN-inducible negative feedback regulator to suppress IFN-I signaling during vesicular stomatitis virus (VSV) infection. Mechanistically, VANGL2 interacted with TBK1 and promoted the selective autophagic degradation of TBK1 via K48-linked polyubiquitination at Lys 372 by the E3 ligase TRIP, which serves as a recognition signal for the cargo receptor OPTN. Furthermore, myeloid-specific deletion of VANGL2 in mice showed enhanced IFN-I production against VSV infection and improved survival. In general, these findings revealed a negative feedback loop of IFN-I signaling through the VANGL2-TRIP-TBK1-OPTN axis and highlighted the cross-talk between IFN-I and autophagy in preventing viral infection. VANGL2 could be a potential clinical therapeutic target for viral infectious diseases, including COVID-19.

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Section: Discussionmentioning

confidence: 83%

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Xie

et al. 2023

Sci. Adv.

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“…Glycosylation of CD82 by the glycosyltransferase MGAT3 is pivotal to disrupt integrin α5β1-mediated cellular adhesion and cytoskeleton rearrangements [ 22 ]. Palmitoylation and phosphorylation of TSPAN8 have been reported to facilitate its nucleus translocation, which enhances the chromatin occupancy of STAT3 transcription factor [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…TSPAN8 + melanoma cells have elevated active MMP-3 and low TIMP-1 levels to promote keratinocyte-originated proMMP-9 activation process, collagen IV degradation and dermal colonization [ 46 ]. Interestingly, the nuclear localization of TSPAN8 can be detected in multiple cancer cells, which involves the formation of TSPAN8-cholesterol-14-3-3θ-importin β complex after being palmitoylated [ 47 ]. The same group further demonstrated that nuclear TSPAN8 could interact with STAT3 to enhance its chromatin occupancy [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

The versatile roles of testrapanins in cancer from intracellular signaling to cell–cell communication: cell membrane proteins without ligands

et al. 2023

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The tetraspanins (TSPANs) are a family of four-transmembrane proteins with 33 members in mammals. They are variably expressed on the cell surface, various intracellular organelles and vesicles in nearly all cell types. Different from the majority of cell membrane proteins, TSPANs do not have natural ligands. TSPANs typically organize laterally with other membrane proteins to form tetraspanin-enriched microdomains (TEMs) to influence cell adhesion, migration, invasion, survival and induce downstream signaling. Emerging evidence shows that TSPANs can regulate not only cancer cell growth, metastasis, stemness, drug resistance, but also biogenesis of extracellular vesicles (exosomes and migrasomes), and immunomicroenvironment. This review summarizes recent studies that have shown the versatile function of TSPANs in cancer development and progression, or the molecular mechanism of TSPANs. These findings support the potential of TSPANs as novel therapeutic targets against cancer.

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“…The plasma membrane protein Tspan8, which contains 4 transmembrane domains, was found to translocate from the plasma membrane to the nucleus. Mechanistically, it is not in the form of vesicles, but rather a Tspan8-cholesterol complex to be translocated into nuclei, and cholesterol is critical for binding and protecting the hydrophobic transmembrane domains of Tspan8 during the translocation process ( 28 ), which suggests another mechanism of plasma membrane protein internalization mediated by a nonspecific transporter, such as cholesterol. Moreover, the canonical STING translocates from the endoplasmic reticulum membrane to the perinuclear area to activate TBK1 and IRF3 upon binding cGAMP, and the translocator in the endoplasmic reticulum composed of TRAPβ, Sec61β, and Sec5 ( 11 , 29 ) contributes to the translocation of STING, whereas iRhom2 facilitates the assembly of the STING-TRAPβ translocation complex ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP

Li¹,

Zhu²,

Zhang³

et al. 2022

Journal of Clinical Investigation

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It has been revealed that 2'3'-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of interferon genes (STING), elicits an antitumoral immune response. Since cGAMP cannot cross the cell membrane, it is not clear how intracellular STING has been activated by extracellular cGAMP until SLC19A1 was identified as an importer to transport extracellular cGAMP into cytosol. However, SLC19A1 deficient cells also sense extracellular cGAMP, suggesting the presence of mechanisms other than the facilitating transporters for STING sensing extracellular cGAMP. Here, we identified an alternatively spliced STING isoform (plasmatic membrane STING, pmSTING) that localized in the plasma membrane with its Cterminus outside the cell, due to lack of one transmembrane domain in its N-terminus compared to canonical STING, by using immunoprecipitation, immunofluorescence and flow cytometry. Further studies showed that extracellular cGAMP not only promoted the dimerization of pmSTING and interaction of pmSTING with Tankbinding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), but also enhanced the phosphorylation of TBK1 and IRF3 and production of interferon in pmSTING transfected cells. Additionally, we also identified similar pmSTING isoforms in other species including human. This study suggests a conserved role for pmSTING in sensing extracellular cGAMP and provides insight into cGAMP's role as an immunotransmitter.

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Nuclear translocation of the 4-pass transmembrane protein Tspan8

Cited by 14 publications

References 11 publications

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

The versatile roles of testrapanins in cancer from intracellular signaling to cell–cell communication: cell membrane proteins without ligands

An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP

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