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Stimulation of hepatocytic AMP-activated protein kinase by okadaic acid and other autophagy-suppressive toxins

SAMARI, Hamid R., MØLLER, Michael T. N., HOLDEN, Lise, ASMYHR, Tonje, SEGLEN, Per O.·2005·Biochemical Journal
DOI 10.1042/bj20040609
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Abstract

Autophagic activity in isolated rat hepatocytes is strongly suppressed by OA (okadaic acid) and other PP (protein phosphatase)-inhibitory toxins as well as by AICAR (5-aminoimidazole-4-carboxamide riboside), a direct activator of AMPK (AMP-activated protein kinase). To investigate whether AMPK is a mediator of the effects of the toxin, a phosphospecific antibody directed against the activation of phosphorylation of the AMPK α (catalytic)-subunit at Thr172 was used to assess the activation status of this enzyme. AICAR as well as all the toxins tested (OA, microcystin-LR, calyculin A, cantharidin and tautomycin) induced strong, dose-dependent AMPKα phosphorylation, correlating with AMPK activity in situ (in intact hepatocytes) as measured by the AMPK-dependent phosphorylation of acetyl-CoA carboxylase at Ser79. All treatments induced the appearance of multiple, phosphatase-sensitive, low-mobility forms of the AMPK α-subunit, consistent with phosphorylation at several sites other than Thr172. The flavonoid naringin, an effective antagonist of OA-induced autophagy suppression, inhibited the AMPK phosphorylation and mobility shifting induced by AICAR, OA or microcystin, but not the changes induced by calyculin A or cantharidin. AMPK may thus be activated both by a naringin-sensitive and a naringin-resistant mechanism, probably involving the PPs PP2A and PP1 respectively. Neither the Thr172-phosphorylating protein kinase LKB1 nor the Thr172-dephosphorylating PP, PP2C, were mobility-shifted after treatment with toxins or AICAR, whereas a slight mobility shifting of the regulatory AMPK β-subunit was indicated. Immunoblotting with a phosphospecific antibody against pSer108 at the β-subunit revealed a naringin-sensitive phosphorylation induced by OA, microcystin and AICAR and a naringin-resistant phosphorylation induced by calyculin A and cantharidin, suggesting that β-subunit phosphorylation could play a role in AMPK activation. Naringin antagonized the autophagy-suppressive effects of AICAR and OA, but not the autophagy suppression caused by cantharidin, consistent with AMPK-mediated inhibition of autophagy by toxins as well as by AICAR.

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  • Thr172 phosphorylation and AMPK activation can be enhanced by PRKDC-mediated phosphorylation of PRKAG1/AMPKγ1, which promotes lysosomal localization of the AMPK complex.

    “Moreover, Thr172 phosphorylation and AMPK activation can be enhanced by PRKDC (protein kinase, DNA-activated, catalytic subunit)mediated phosphorylation of PRKAG1/AMPKγ1, which promotes the lysosomal localization of the AMPK complex [650].”

    From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [650]

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Metadata

Authors
SAMARI, H. R., MØLLER, M. T. N., HOLDEN, L., ASMYHR, T., & SEGLEN, P. O.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2005-02-22
Volume
386
Issue
2
Pages
237-244
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20040609
Cited by
58
References
4
Language
en

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