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Modulation of lysosomal function as a therapeutic approach for coronaviral infections
Author(s) -
Lear Travis,
Larsen Mads,
Lin Bo,
Cao Qing,
Alfaras Irene,
Kennerdell Jason,
Salminen Laura,
Camarco Daniel,
Lockwood Karina C.,
Boudreau Áine,
Ma Jing,
Liu Jie,
Tan Jay X.,
Myerburg Michael M.,
Chen Yanwen,
St Croix Claudette,
Sekine Yusuke,
Evankovich John,
Finkel Toren,
Chen Bill B.,
Liu Yuan
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r5136
Subject(s) - tfeb , ubiquitin ligase , microbiology and biotechnology , ubiquitin , biology , lysosome , nedd4 , hek 293 cells , chemistry , virology , biochemistry , cell culture , genetics , enzyme , gene
The endo‐lysosomal pathway plays an important role in pathogen clearance and both bacteria and viruses have evolved complex mechanisms to evade this host system. Here, we describe a novel aspect of coronaviral infection, whereby the master transcriptional regulator of lysosome biogenesis – TFEB – is targeted for proteasomal‐mediated degradation upon viral infection. Through mass spectrometry analysis and an unbiased siRNA screen, we identify that TFEB protein stability is coordinately regulated by the E3 ubiquitin ligase subunit DCAF7 and the PAK2 kinase. In particular, viral infection triggers marked PAK2 activation, which in turn, phosphorylates and primes TFEB for ubiquitin‐mediated protein degradation. Deletion of either DCAF7 or PAK2 blocks viral‐mediated TFEB degradation and protects against viral‐induced cytopathic effects. We further derive a series of small molecules that interfere with the DCAF7‐TFEB interaction. These agents inhibit viral‐triggered TFEB degradation and demonstrate broad anti‐viral activities including attenuating in vivo SARS‐CoV‐2 infection. Together, these results delineate a viral‐triggered pathway that disables the endogenous cellular system that maintains lysosomal function and suggest that small molecule inhibitors of the E3 ubiquitin ligase DCAF7 represent a novel class of endo‐lysosomal, host‐directed, anti‐viral therapies.