AI Article Synopsis

  • Coronaviruses disrupt cilia function by targeting a host protein called septin, which is essential for cilia structure and operation.
  • This disruption leads to the cleavage of specific septin proteins, resulting in obstructions that affect ciliogenesis and Sonic Hedgehog (SHH) signaling pathways.
  • The use of 3CL protease inhibitors shows promise in preventing these ciliary defects and could be effective therapeutics for treating complications associated with coronavirus infections.

Article Abstract

Coronaviruses target ciliate cells causing the loss of cilia, acute rhinorrheas, and other ciliopathies. The loss of ciliary function may help the virus infect, replicate, and spread. However, the molecular mechanisms by which coronaviruses cause ciliary defects are still unclear. Herein we demonstrate how coronavirus infection and severe acute respiratory syndrome coronavirus2 3CL protease induce cilia dysfunction by targeting a host protein septin that is required for the structure and function of cilia. Further, we demonstrate that coronaviruses and 3CL protease lead to the cleavage of several septin proteins (SEPT2, -6, and -9), producing cleaved obstructive fragments. Furthermore, ectopic expression of cleaved SEPT2 fragments shows defective ciliogenesis, disoriented septin filaments, and ablated Sonic Hedgehog (SHH) signaling in a protease activity-dependent manner. We present that the 3CLpro inhibitors are potent and prevent abnormal ciliary structures and SHH signaling. These results provide useful insights into the general mechanisms underlying ciliary defects caused by coronaviruses, which, in turn, facilitate virus spread and prove that preclinical and clinical 3CL protease inhibitors may prove useful as therapeutics for treating ciliary defects of coronaviruses.

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http://dx.doi.org/10.1002/jmv.28618DOI Listing

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