UNC-45A is required for neurite extension via controlling NMII activation

Iizuka, Yoshie; Mooneyham, Ashley; Sieben, Andrew; Chen, Kevin; Maile, Makayla; Hellweg, Raffaele; Schütz, Florian; Teckle, Kebebush; Starr, Timothy K.; Thayanithy, Venugopal; Lou, Emil; Lee, Michael K.; Bazzaro, Martina

doi:10.1091/mbc.e16-06-0381

Cited by 17 publications

(23 citation statements)

References 39 publications

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“…Most of the studies published so far on the mammalian isoform UNC-45A have focused on its role as direct or indirect regulator of actomyosin contractility. This includes studies from our laboratories showing that UNC-45A co-localizes with NMII in mammalian cells including cancer cells, NK cells and neurons [17,19,20]. This also includes a study from Dr. Lappalainen's group showing that the UCS domain of UNC-45A co-localizes with stress fibers in the U2OS cell line where it promotes myosin folding and stress fibers assembly [6].…”

Section: Discussionmentioning

confidence: 99%

“…Third, fixation methods other than cold methanol (which we have used here and previously to show that UNC-45A is a MAP [5]) may not be suitable for MT localization or co-localization studies because their either do not preserve MTs well, or interfere with antigen binding. With regards to this point, our work on co-localization of UNC-45A with NMII in NK cells and neurons [17,19,20] as well work from Drs. Lappalainen and Chadli's groups were all done using formaldehyde fixation because that is the preferred method for studying the actomyosin system.…”

Section: Discussionmentioning

confidence: 99%

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UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs

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Mooneyham

Shetty

et al. 2019

Preprint

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max 250)UNC-45A is a ubiquitously expressed protein highly conserved throughout evolution.Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system. However, emerging studies from both our and other laboratories support a role of UNC-45A outside of actomyosin regulation. This includes studies showing that UNC-45A:regulates gene transcription, co-localizes and biochemically co-fractionates with gamma tubulin and regulates centrosomal positioning, is found in the same subcellular fractions where MTassociated proteins are, and is a mitotic spindle-associated protein with MT destabilizing activity in absence of the actomyosin system.Here, we extended our previous findings and show that UNC45A is variably expressed across a spectrum of cell lines with the highest level being found in HeLa cells and in ovarian cancer cells inherently paclitaxel-resistant. Furthermore, we show that UNC-45A is preferentially expressed in epithelial cells, localizes to mitotic spindles in clinical tumor specimens of cancer and co-localizes and co-fractionates with MTs in interphase cells independent of actin or myosin.In sum, we report alteration of UNC45A localization in the setting of chemotherapeutic treatment of cells with paclitaxel, and localization of UNC45A to MTs both in vitro and in vivo.These findings will be important to ongoing and future studies in the field that further identify the important role of UNC45A in cancer and other cellular processes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs

Habicht

Mooneyham

Shetty

et al. 2019

Preprint

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“…For UNC-45A silencing and overexpression scramble and UNC-45A shRNAs lentiviral supernatant or empty vector control and UNC-45A-GFP lentiviral supernatants were prepared and used to infect RFL-6 cells as we have previously described [11,12,22]. For ectopic expression, RFL-6 or U2OS cells were infected with lentiviral particle carrying FLAG only (control) or FLAG-tagged UNC-45A WT, deltaN and deltaC and expression levels were evaluated 24-or 48-hours post infection.…”

Section: Modulation Of Unc-45a and Katanin Expression Levels In Cellsmentioning

confidence: 99%

“…We and others have shown that in mammalian cells, UNC-45A binds to and co-localizes with Non-Muscle Myosin II (NMII) [11][12][13] and the C-terminal NMII-binding domain of UNC-45A is required for myosin II folding, myosin II binding with actin [14,15], and stress fiber assembly [16]. This includes studies from our laboratory showing that UNC-45A plays a role in regulating NMII-assisted functions including cytokinesis [13], exocytosis in immune cells [11], axonal growth of neurons [17] and tunneling nanotube formation [18].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly to and perhaps because of its worm homolog UNC-45, UNC-45A has been mostly studied in the context of its role in regulating NMII activity. This includes studies from our and other groups showing that UNC-45A binds to and co-localizes with NMII and regulates its activity including the formation of stress fibers [11][12][13][14]16]. Over the past five years however, it became evident that UNC-45A also regulates MT stability.…”

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UNC-45A Weakens and Breaks MT Lattice Independent of its Effect on Non-Muscle Myosin II

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Mooneyham

Shetty

et al. 2020

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In invertebrates, the member of UCS domain family UNC-45 regulates myosin stability and functions. Vertebrates have two distinct isoforms of the protein: UNC-45B, expressed in muscle cells only and responsible for muscle myosin folding and assembly, and UNC-45A, expressed in all cells and implicated in regulating both Non-Muscle Myosin II (NMII)-and microtubule (MT)-associated functions. Here we show for the first time that in vitro UNC-45A binds to the lattice of paclitaxel-stabilized MTs, and destabilizes the lattice integrity, leading to MT depolymerization in a dose-dependent manner. We also show that UNC-45A overexpression causes a dramatic loss of MT mass and increase in MT breakages in cells lacking the MT stabilizing protein tau. We also show for the first time that, both in vitro and in cells, that UNC-45A destabilizes MTs independent of its NMII C-terminal binding domain and destabilization occurs even in presence of the NMII inhibitor blebbistatin. These findings are consistent with a not mutually exclusive but rather dual role of UNC-45A in regulating NMII activity and MT stability. As many human diseases, from cancer to neurodegenerative diseases are caused by or associated with deregulation of MT stability, our findings are important as to ongoing and future studies aimed to understand the mechanisms through which UNC-45A regulates MT stability in the context of health and disease. This includes providing a novel platform for therapeutic intervention of cancer and neurodegenerative diseases.

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Beyond Chaperoning: UCS Proteins Emerge as Regulators of Myosin-Mediated Cellular Processes

Odunuga

Oberhauser

2022

Subcellular Biochemistry

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UNC-45A is required for neurite extension via controlling NMII activation

Cited by 17 publications

References 39 publications

UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs

UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs

UNC-45A Weakens and Breaks MT Lattice Independent of its Effect on Non-Muscle Myosin II

Beyond Chaperoning: UCS Proteins Emerge as Regulators of Myosin-Mediated Cellular Processes

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