Afadin is a scaffold protein repressing insulin action via HDAC6 in adipose tissue
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Afadin is a scaffold protein repressing insulin action via HDAC6 in adipose tissue. / Lundh, Morten; Petersen, Patricia Ss; Isidor, Marie S; Kazoka-Sørensen, Dolly Nm; Plucińska, Kaja; Shamsi, Farnaz; Ørskov, Cathrine; Tozzi, Marco; Brown, Erin L; Andersen, Emil; Ma, Tao; Müller, Ulrich A.; Barrès, Romain; Kristiansen, Viggo B; Gerhart-Hines, Zachary; Tseng, Yu-Hua; Emanuelli, Brice.
I: EMBO Reports, Bind 20, Nr. 8, e48216, 2019.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Afadin is a scaffold protein repressing insulin action via HDAC6 in adipose tissue
AU - Lundh, Morten
AU - Petersen, Patricia Ss
AU - Isidor, Marie S
AU - Kazoka-Sørensen, Dolly Nm
AU - Plucińska, Kaja
AU - Shamsi, Farnaz
AU - Ørskov, Cathrine
AU - Tozzi, Marco
AU - Brown, Erin L
AU - Andersen, Emil
AU - Ma, Tao
AU - Müller, Ulrich A.
AU - Barrès, Romain
AU - Kristiansen, Viggo B
AU - Gerhart-Hines, Zachary
AU - Tseng, Yu-Hua
AU - Emanuelli, Brice
PY - 2019
Y1 - 2019
N2 - Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine-tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell-autonomous and phosphorylation-dependent manner. Insulin-stimulated Afadin-S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue-specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet-induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin-induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.
AB - Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine-tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell-autonomous and phosphorylation-dependent manner. Insulin-stimulated Afadin-S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue-specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet-induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin-induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.
U2 - 10.15252/embr.201948216
DO - 10.15252/embr.201948216
M3 - Journal article
C2 - 31264358
VL - 20
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 8
M1 - e48216
ER -
ID: 225475736