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Review 1: "MX2 Restricts HIV-1 and Herpes Simplex Virus Type 1 by Forming Cytoplasmic Biomolecular Condensates that Mimic Nuclear Pore Complexes"

Reviewers found the study compelling, clearly demonstrating the mechanism by which MX2 forms cytoplasmic condensates with host factors to trap viral capsids and prevent proper nuclear targeting by HIV-1 and HSV-1.

Published onMay 08, 2024
Review 1: "MX2 Restricts HIV-1 and Herpes Simplex Virus Type 1 by Forming Cytoplasmic Biomolecular Condensates that Mimic Nuclear Pore Complexes"
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MX2 restricts HIV-1 and herpes simplex virus type 1 by forming cytoplasmic biomolecular condensates that mimic nuclear pore complexes
MX2 restricts HIV-1 and herpes simplex virus type 1 by forming cytoplasmic biomolecular condensates that mimic nuclear pore complexes
Description

Summary Human myxovirus resistance 2 (MX2) can potently restrict HIV-1 and herpesviruses at a post-entry step by a process that requires MX2 interaction with the capsids of these viruses. The involvement of other host cell factors in this process, however, remains poorly understood. Here, we mapped the proximity interactome of MX2 revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacted with these proteins to form multiprotein cytoplasmic biomolecular condensates that were essential for its anti-HIV-1 and -herpes simplex virus-1 (HSV-1) activity. MX2 condensate formation required the disordered N-terminal region of MX2 and its dimerization. Incoming HIV-1 and HSV-1 capsids associated with MX2 at these dynamic cytoplasmic biomolecular condensates. Our results demonstrate that MX2 forms cytoplasmic condensates that act as nuclear pore decoys, which trap capsids and induce premature viral genome release, and thereby interfere with nuclear targeting of HIV-1 and HSV-1.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: The authors investigate the function of the IRG MX2 in resisting infection by the human lentivirus HIV-1 and human herpesvirus HSV-1. They identify regions of the MX2 molecule that are important for interacting with host factors to form cytoplasmic biomolecular condensates that act as a decoy to prevent viral capsids from binding to the nuclear pores of infected cells.

In the manuscript, the authors have investigated, in depth, how the human myxovirus resistance 2 (MX2) molecules, activated in cells in response to interferon (hence, an interferon response gene – IRG), is able to restrict infection of human lentivirus (HIV-1) and human herpesvirus (HSV-1). The authors have provided a strong testable hypothesis, and a detailed experimental plan that addresses protein interactions using proteomics, functional interactions through the demonstration of antiviral activity of the authentic and mutant forms of MX2, and cell imaging level, to demonstrate the interaction between MX2 molecules with identified host factors, resulting in the targeting of incoming virions to cytoplasmic biomolecular condensates containing molecules usually associated with the nuclear pores. The authors have done an outstanding job of identifying the regions of the MX2 molecules important for the interactions with the host factors, and have distinguished between the functions involved in inhibiting HIV-1 infections, and the distinct functions involved in the inhibition of HSV-1 infections. The experimental designs and presentation of the findings is outstanding, while very dense in presentation. The conclusions reached are strongly supported by the presented data, and the discussion is thoughtfully written. The study provides an important step forward in the knowledge regarding the function and versatility of the MX2 protein in antiviral responses.

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