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PRRSV utilizes MALT1-regulated autophagy flux to switch virus spread and reserve

Han Gu1,2,3, He Qiu1,2,3, Haotian Yang1,2,3

  • 1MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China.

Autophagy
|July 31, 2024
PubMed

Insights

Porcine reproductive and respiratory syndrome virus (PRRSV) manipulates MALT1 to control autophagy flux, influencing viral proliferation and persistence. MALT1 inhibition blocks viral spread by disrupting autophagosome-lysosome fusion.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant swine pathogen.
  • PRRSV manipulates host antiviral immunity and induces autophagy to facilitate replication.
  • MALT1 (MALT1 paracaspase) is a key immune regulator targeted by PRRSV.

Purpose of the Study:

  • To characterize the role of MALT1 in regulating autophagy during PRRSV infection.
  • To elucidate how MALT1 influences autophagy flux and viral proliferation.
  • To understand the mechanisms by which MALT1 controls viral fate (proliferation vs. reserve).

Main Methods:

  • Investigated MALT1's role in PRRSV-induced autophagy using MALT1 inhibitors (Mi-2) and RNA interference (RNAi).
  • Assessed autophagy flux, autophagosome-lysosome fusion, and lysosomal homeostasis.
  • Examined signaling pathways including MTOR-ULK1 and TFEB.
  • Evaluated the impact of MALT1 manipulation on viral replication and release.
  • Measured reactive oxygen species (ROS) generation and lysosomal membrane permeabilization (LMP).

Main Results:

  • PRRSV infection induces autophagy, which enhances virus proliferation.
  • MALT1 facilitates autophagosome-lysosome fusion and autolysosome formation, promoting autophagy flux.
  • MALT1 regulates autophagy via MTOR-ULK1 and TFEB signaling, impacting lysosomal homeostasis.
  • MALT1 inhibition leads to lysosomal membrane permeabilization (LMP) and blocks autophagic fusion.
  • MALT1 overexpression inhibits ROS generation and alleviates PRRSV-induced LMP.
  • Blocking autophagy flux significantly suppresses PRRSV release.

Conclusions:

  • MALT1 is crucial for maintaining complete autophagy flux during PRRSV infection, favoring virus spread and proliferation.
  • PRRSV utilizes MALT1 to regulate autophagy flux, determining the virus's fate for proliferation or reserve.
  • MALT1 inhibition offers a potential strategy to control PRRSV spread by disrupting viral replication mechanisms.
Keywords:
Autophagy fluxLMPMALT1MTORPRRSVlysosome homeostasis

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