TMEM16E (GDD1) Exhibits Protein Instability and Distinct Characteristics in Chloride Channel/Pore Forming Ability. Issue 2 (25th October 2013)

• Record Type: Journal Article
• Authors: Tran, Ta To; Tobiume, Kei; Hirono, Chikara; Fujimoto, Shinichi; Mizuta, Kuniko; Kubozono, Kazumi; Inoue, Hiroshi; Itakura, Mitsuo; Sugita, Makoto; Kamata, Nobuyuki
• Is Part Of: Journal of cellular physiology. Volume 229:Issue 2(2014:Feb.)
• Page Start: 181
• Page End: 190
• Publication Date: 2013-10-25
• Subjects: Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.24431
• Languages: English
• ISSNs: 0021-9541

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcp24431-sec-0001" sec-type="section"> <p>TMEM16E/GDD1 has been shown to be responsible for the bone‐related late‐onset disease gnathodiaphyseal dysplasia (GDD), with the dominant allele (<italic>TMEM16E</italic><sup><italic>gdd</italic></sup>) encoding a missense mutation at Cys356. Additionally, several recessive loss‐of‐function alleles of <italic>TMEM16E</italic> also cause late‐onset limb girdle muscular dystrophy. In this study, we found that TMEM16E was rapidly degraded via the proteasome pathway, which was rescued by inhibition of the PI3K pathway and by the chemical chaperone, sodium butyrate. Moreover, TMEM16E<sup>gdd</sup> exhibited lower stability than TMEM16E, but showed similar propensity to be rescued. TMEM16E did not exhibit cell surface calcium‐dependent chloride channel (CaCC) activity, which was originally identified in TMEM16A and TMEM16B, due to their intracellular vesicle distribution. A putative pore‐forming domain of TMEM16E, which shared 39.8% similarity in 98 amino acids with TMEM16A, disrupted CaCC activity of TMEM16A via domain swapping. However, the Thr611Cys mutation in the swapped domain, which mimicked conserved cysteine residues between TMEM16A and TMEM16B, reconstituted CaCC activity. In addition, the GDD‐causing cysteine mutation made in TMEM16A drastically altered CaCC activity. Based on these findings, TMEM16E possesses distinct function other than CaCC and another protein‐stabilizing machinery toward the TMEM16E and TMEM16E<sup>gdd</sup> proteins should be considered for the on‐set regulation of their phenotypes in tissues. J. Cell. Physiol. 229: 181–190, 2014. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>