Uropathogenic Escherichia coli invades host cells via an HDAC6-modulated microtubule-dependent pathway.
Strains of uropathogenic Escherichia coli (UPEC) encode filamentous adhesive organelles called type 1 pili that promote bacterial colonization and invasion of the bladder epithelium. Type 1 pilus-mediated interactions with host receptors, including alpha3beta1 integrin, trigger localized actin rearrangements that lead to internalization of adherent bacteria via a zipper-like mechanism. Here we report that type 1 pilus-mediated bacterial invasion of bladder cells also requires input from host microtubules and histone deacetylase 6 (HDAC6), a cytosolic enzyme that, by deacetylating alpha-tubulin, can alter the stability of microtubules along with the recruitment and directional trafficking of the kinesin-1 motor complex. We found that disruption of microtubules by nocodazole or vinblastine treatment, as well as microtubule stabilization by taxol, inhibited host cell invasion by UPEC, as did silencing of HDAC6 expression or pharmacological inhibition of HDAC6 activity. Invasion did not require two alternate HDAC6 substrates, Hsp90 and cortactin, but was dependent upon the kinesin-1 light chain KLC2 and an upstream activator of HDAC6, aurora A kinase. These results indicate that HDAC6 and microtubules act as vital regulatory elements during the invasion process, possibly via indirect effects on kinesin-1 and associated cargos.
Dhakal
Bijaya K
BK
Division of Cell Biology and Immunology, Pathology Department, University of Utah, Salt Lake City, Utah 84112-0565.
Mulvey
Matthew A
MA
Division of Cell Biology and Immunology, Pathology Department, University of Utah, Salt Lake City, Utah 84112-0565. Electronic address: mulvey@path.utah.edu.
D000107:Acetylation / Q000187:drug effects; D000199:Actins / Q000235:genetics / Q000378:metabolism; D064127:Aurora Kinases; D001422:Bacterial Adhesion / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D051356:Cortactin / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000382:microbiology; D004926:Escherichia coli / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism*; D010861:Fimbriae, Bacterial / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D001743:Urinary Bladder / Q000378:metabolism / Q000382:microbiology; D001745:Urinary Bladder Diseases / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology
D000199:Actins; D051356:Cortactin; D018841:HSP90 Heat-Shock Proteins; D039201:Integrin alpha3beta1; D014404:Tubulin; D050257:Tubulin Modulators; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D016547:Kinesins