Human coronavirus 3CL proteases cleave septins and disrupt Hedgehog signaling, causing ciliary dysfunction

Area of Science:

• Virology
• Cell Biology
• Molecular Mechanisms

Background:

• Coronaviruses induce ciliopathies like acute rhinorrhea by targeting ciliate cells.
• The precise molecular pathways linking coronavirus infection to ciliary dysfunction remain largely unknown.
• Ciliary dysfunction may facilitate viral infection, replication, and spread.

Purpose of the Study:

• To elucidate the molecular mechanisms by which coronaviruses cause ciliary defects.
• To investigate the role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease in inducing cilia dysfunction.
• To evaluate the therapeutic potential of 3CL protease inhibitors against coronavirus-induced ciliopathies.

Main Methods:

• Investigated coronavirus-induced effects on host septin proteins essential for cilia structure and function.
• Analyzed the cleavage of specific septin proteins (SEPT2, -6, -9) by coronaviruses and 3CL protease.
• Examined the impact of expressing cleaved SEPT2 fragments on ciliogenesis, septin filament organization, and Sonic Hedgehog (SHH) signaling.
• Assessed the efficacy of 3CL protease inhibitors in preventing ciliary abnormalities and SHH pathway disruption.

Main Results:

• Coronavirus infection and SARS-CoV-2 3CL protease induce cilia dysfunction by targeting septins.
• Both coronaviruses and 3CL protease cleave SEPT2, SEPT6, and SEPT9, generating obstructive fragments.
• Expression of cleaved SEPT2 fragments impairs ciliogenesis, disorients septin filaments, and inhibits SHH signaling in a protease-dependent manner.
• 3CL protease inhibitors effectively prevent abnormal ciliary structures and SHH signaling disruption.

Conclusions:

• Coronaviruses and their 3CL protease induce ciliary defects through septin cleavage, contributing to viral spread.
• Preclinical and clinical 3CL protease inhibitors show promise as therapeutics for treating coronavirus-associated ciliopathies.
• Understanding these mechanisms provides insights into broader viral pathogenesis and potential treatment strategies.