PSGL-1 inhibits HIV-1 infection by restricting actin dynamics and sequestering HIV envelope proteins

Liu, Ying; Song, Yinglin; Zhang, Siyu; Diao, Min; Huang, Shanjin; Li, Sai; Tan, Xu

doi:10.1038/s41421-020-0184-9

Cited by 17 publications

(24 citation statements)

References 44 publications

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“…The anti-HIV activity of PSGL-1 is mainly attributed to its incorporation into virion particles that sterically hinders virion attachment to target cells (Fu et al, 2020; Murakami et al, 2020). In addition, virion incorporation of PSGL-1 also inhibits the incorporation of the HIV-1 Env protein (Fu et al, 2020; Liu et al, 2020). To study the anti-viral mechanisms of SHREK, we examined virion incorporation of SHERK proteins.…”

Section: Resultsmentioning

confidence: 99%

Identification of the SHREK family of proteins as broad-spectrum host antiviral factors

Dabbagh

Hetrick

et al. 2021

Preprint

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Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123), that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 virus-like particle. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.

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Section: Resultsmentioning

confidence: 99%

Identification of the SHREK family of proteins as broad-spectrum host antiviral factors

Dabbagh

Hetrick

et al. 2021

Preprint

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“…Therefore, Env proteins without a CT could be easily released due to abundant PM localization, although potential host factors that may influence this process warrant further exploration. For example, Ying Liu et al reported that the host protein P-selectin glycoprotein ligand 1 (PSGL-1) sequesters Env of HIV-1 at the PM by binding to gp41 ( 49 ). In addition, some studies have shown that Envs of HIV-1 release culture supernatant from HIV-1-infected cells or cells transfected with Env through the extracellular vesicle pathway ( 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

Truncation of the Cytoplasmic Tail of Equine Infectious Anemia Virus Increases Virion Production by Improving Env Cleavage and Plasma Membrane Localization

Wang

Bai

et al. 2021

J Virol

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Envelope glycoproteins (Envs) of lentiviruses harbor unusually long cytoplasmic tails (CTs). Natural CT truncations always occur in vitro and are accompanied by attenuated virulence, but their effects on viral replication have not been fully elucidated. The Env in equine infectious anemia virus (EIAV) harbors the longest CT in the lentiviral family, and a truncated CT was observed in a live attenuated vaccine. This study demonstrates that CT truncation significantly increased EIAV production, as determined by comparing the virion yields from EIAV infectious clones in the presence or absence of the CT. A significant increase in a cleaved product from the CT-truncated Env precursor, but not the full-length Env, was observed. We further confirmed that the presence of the CT inhibited the cleavage of the Env precursor and found that a functional domain located at the C-terminus was responsible for this function. Moreover, CT-truncated Env was mainly localized at the plasma membrane (PM), while full-length Env was mainly localized in the cytoplasm. The CT-truncation caused a dramatic reduction in the endocytosis of Env. These results suggest that the CT can modulate the processing and trafficking of EIAV Env and thus regulate EIAV replication. Importance The mature lentivirus envelope glycoprotein (Env) is composed of a surface unit (SU) and a transmembrane unit (TM), which are cleaved products of the Env precursor. After mature Env is heterodimerically formed from the cleavage of the Env precursor, it is trafficked to the plasma membrane (PM) for incorporation and virion assembly. Env harbors a long cytoplasmic tail (CT), which has been increasingly found to play multiple roles in the Env biological cycle. Here, we revealed for the first time that the CT of equine infectious anemia virus (EIAV) Env inhibits cleavage of the Env precursor. Simultaneously, the CT promoted Env endocytosis, resulting in weakened Env localization at the PM. We also validated that the CT could significantly decrease EIAV production. These findings suggest that the CT regulates the processing and trafficking of EIAV Env to balance virion production.

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“…conserved threonine (T393) was identified as a key residue for the binding of PSGL-1 to actin. Subsequently, PSGL-1's inhibition of reverse transcription and ability to increase Factin intensity were greatly reduced by a T393 mutation (97). This represents PSGL-1's early inhibition role in HIV-1 infection, and is a plausible explanation for this process as it is known that an actin cytoskeleton is required for HIV reverse transcription (107).…”

Section: Streptococcus Pneumoniaementioning

confidence: 84%

“…This observation was revealed one month earlier via an e-publication by a Japanese team of researchers (106), who also demonstrated that co-clustering of Gag with PSGL-1 [previously shown to be dependent on the MA domain, especially the HBR (27)] and subsequent release of progeny virions, promote extracellular PSGL-1 down-regulation in infected cells. Very recently (August 2020), Liu et.al (97)., revealed a series of findings showing that PSGL-1 binds to cellular actin filaments (F-actin) to restrict actin dynamics, which consequently inhibit HIV-1 DNA synthesis and HIV-1 reverse transcription (Figure 3). Of note, PSGL-1's inhibition of HIV-1 reverse transcription is dependent on the cytoplasmic domain, which by itself is sufficient for the inhibition.…”

Section: Streptococcus Pneumoniaementioning

confidence: 99%

P-Selectin Glycoprotein Ligand 1: A Potential HIV-1 Therapeutic Target

Zaongo

Harypursat

et al. 2021

Front. Immunol.

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Antiretroviral therapy (ART), which is a life-long therapeutic option, remains the only currently effective clinical method to treat HIV-1 infection. However, ART may be toxic to vital organs including the liver, brain, heart, and kidneys, and may result in systemic complications. In this context, to consider HIV-1 restriction factors from the innate immune system to explore novel HIV therapeutics is likely to be a promising investigative strategy. In light of this, P-selectin glycoprotein ligand 1 (PSGL-1) has recently become the object of close scrutiny as a recognized cell adhesion molecule, and has become a major focus of academic study, as researchers believe that PSGL-1 may represent a novel area of interest in the research inquiry into the field of immune checkpoint inhibition. In this article, we review PSGL-1’s structure and functions during infection and/or inflammation. We also outline a comprehensive review of its role and potential therapeutic utility during HIV-1 infection as published in contemporary academic literature.

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PSGL-1 inhibits HIV-1 infection by restricting actin dynamics and sequestering HIV envelope proteins

Cited by 17 publications

References 44 publications

Identification of the SHREK family of proteins as broad-spectrum host antiviral factors

Identification of the SHREK family of proteins as broad-spectrum host antiviral factors

Truncation of the Cytoplasmic Tail of Equine Infectious Anemia Virus Increases Virion Production by Improving Env Cleavage and Plasma Membrane Localization

P-Selectin Glycoprotein Ligand 1: A Potential HIV-1 Therapeutic Target

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