ZDHHC3-LYPLA1 regulates PRRSV-2 replication through reversible palmitoylation.

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses in swine production.
• Palmitoylation, a post-translational modification, is implicated in various viral infections.
• The precise role of palmitoylation in PRRSV replication remains largely unexplored.

Purpose of the Study:

• To investigate the role of protein palmitoylation in regulating PRRSV replication.
• To identify key enzymes involved in the palmitoylation pathway affecting PRRSV.

Main Methods:

• Inhibition of palmitoylation using 2-bromo palmitate (2-BP).
• Identification of ZDHHC3 as the critical palmitoyl transferase.
• Analysis of nucleocapsid (N) protein modification and interactions.
• Assessment of LYPLA1's de-palmitoylating activity.
• Treatment with LYPLA1 inhibitor ML348.

Main Results:

• Inhibition of palmitoylation by 2-BP significantly promotes PRRSV multiplication.
• ZDHHC3 was identified as the key enzyme regulating PRRSV replication in PAMs.
• ZDHHC3-mediated palmitoylation of the N protein at Cys90 inhibits Nsp9-N protein interaction and viral RNA synthesis.
• LYPLA1 de-palmitoylates the N protein, counteracting ZDHHC3 activity.
• The LYPLA1 inhibitor ML348 effectively hinders PRRSV-2 replication.

Conclusions:

• Reversible protein palmitoylation critically regulates PRRSV replication.
• ZDHHC3 and LYPLA1 are key players in controlling PRRSV multiplication through N protein modification.
• Targeting palmitoylation pathways presents a promising avenue for novel anti-PRRSV therapeutic strategies.