A novel proviral mechanism for the ISG, Shiftless, during human coronavirus infection

Abstract

As highly pathogenic human coronaviruses continue to emerge from zoonotic sources, understanding how host intrinsic immune responses control infection is critical for preventing severe disease. The interferon (IFN) pathway induces antiviral effectors, including the interferon-stimulated gene (ISG) Shiftless (SHFL), which restricts -1 programmed ribosomal frameshifting during SARS-CoV-2 infection. Here, we investigate a novel proviral mechanism for SHFL using loss-of-function and gain-of-function approaches. Despite its established antiviral activity, SHFL enhanced infection by SARS-CoV-2 and the seasonal coronavirus HCoV-229E by increasing cellular susceptibility to infection. SHFL further promoted coronavirus infection by reducing cellular sensitivity to IFN, potentially through modulation of JAK/STAT signaling. Finally, we demonstrate that SHFL-mediated enhancement of baseline viral susceptibility is partially dependent on the domain previously implicated in its antiviral inhibition of -1 programmed ribosomal frameshifting. In contrast, SHFL-mediated regulation of IFN signaling is independent of this domain. Together, these findings establish SHFL as a dual-function ISG with distinct proviral and antiviral activities, highlighting the complex roles of innate immune effectors during coronavirus infection.

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BibTeX

@misc{shue2026novel,
  title = {{A novel proviral mechanism for the ISG, Shiftless, during human coronavirus infection}},
  author = {Taylor M Shue and Georgios Mourtzouchos and Dar-Yin Li and Yee T. Ong and Antonis Athanasiadis and Maria Bousali and Madeleine Sanders and Sophie N. Spector and Christopher Rivera-Bonilla and Khadija Ndoye and Kenneth C. Levenson and Jens Cuba and Jayden Harris and Kelly Mieck and Shuiyun Lan and Volker Kinast and Julia LeCher and Jérémie Le Pen and Stefan G. Sarafianos and Eleftherios Michailidis},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.16.759718},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759718v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - A novel proviral mechanism for the ISG, Shiftless, during human coronavirus infection
AU  - Taylor M Shue
AU  - Georgios Mourtzouchos
AU  - Dar-Yin Li
AU  - Yee T. Ong
AU  - Antonis Athanasiadis
AU  - Maria Bousali
AU  - Madeleine Sanders
AU  - Sophie N. Spector
AU  - Christopher Rivera-Bonilla
AU  - Khadija Ndoye
AU  - Kenneth C. Levenson
AU  - Jens Cuba
AU  - Jayden Harris
AU  - Kelly Mieck
AU  - Shuiyun Lan
AU  - Volker Kinast
AU  - Julia LeCher
AU  - Jérémie Le Pen
AU  - Stefan G. Sarafianos
AU  - Eleftherios Michailidis
PY  - 2026
DA  - 2026/10/16
PB  - bioRxiv
DO  - 10.64898/2026.10.16.759718
UR  - https://www.biorxiv.org/content/10.64898/2026.10.16.759718v1
AB  - As highly pathogenic human coronaviruses continue to emerge from zoonotic sources, understanding how host intrinsic immune responses control infection is critical for preventing severe disease. The interferon (IFN) pathway induces antiviral effectors, including the interferon-stimulated gene (ISG) Shiftless (SHFL), which restricts -1 programmed ribosomal frameshifting during SARS-CoV-2 infection. Here, we investigate a novel proviral mechanism for SHFL using loss-of-function and gain-of-function approaches. Despite its established antiviral activity, SHFL enhanced infection by SARS-CoV-2 and the seasonal coronavirus HCoV-229E by increasing cellular susceptibility to infection. SHFL further promoted coronavirus infection by reducing cellular sensitivity to IFN, potentially through modulation of JAK/STAT signaling. Finally, we demonstrate that SHFL-mediated enhancement of baseline viral susceptibility is partially dependent on the domain previously implicated in its antiviral inhibition of -1 programmed ribosomal frameshifting. In contrast, SHFL-mediated regulation of IFN signaling is independent of this domain. Together, these findings establish SHFL as a dual-function ISG with distinct proviral and antiviral activities, highlighting the complex roles of innate immune effectors during coronavirus infection.
SN  - 2692-8205
ER  -

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