Abstract:SUMMARY
AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 … Show more
“…The concept of platforms for assembly of autophagic machinery in mammalian cells also extends to generic, starvation-induced autophagy, which utilizes exocyst components specifically endowed with Exo84 (Bodemann et al, 2011). However, TRIM engagement with autophagy may entail other mechanisms, as for example TRIM28 has multiple (both positive and negative) proposed mechanisms of action (Barde et al, 2013;Yang et al, 2013;Pineda et al, 2015), whereas the mechanism of autophagy induction for TRIM13 in response to the ER stress has not been fully delineated (Tomar et al, 2012), although it shows a relationship with p62 and DFCP, an ER-derived autophagy precursor compartment termed omegasome (Axe et al, 2008).…”
Section: Discussionmentioning
confidence: 99%
“…IFN-γ induces autophagy (Inbal et al, 2002;Gutierrez et al, 2004;Fabri et al, 2011) and influences cytokine networks and polarization of immune systems (Ghezzi and Dinarello, 1988;Schroder and Tschopp, 2010;Mishra et al, 2013), whereas TRIMs are involved in immune responses (Kawai and Akira, 2011) and, through an assortment of proposed mechanisms affect autophagy (Niida et al, 2010;Tomar et al, 2012;Barde et al, 2013;Pizon et al, 2013;Yang et al, 2013;Khan et al, 2014;Mandell et al, 2014;Pineda et al, 2015). IFN-γ can induce expression of a subset of TRIMs (Carthagena et al, 2009).…”
Section: Trims Participate In Ifn-γ-induced Autophagymentioning
“…The concept of platforms for assembly of autophagic machinery in mammalian cells also extends to generic, starvation-induced autophagy, which utilizes exocyst components specifically endowed with Exo84 (Bodemann et al, 2011). However, TRIM engagement with autophagy may entail other mechanisms, as for example TRIM28 has multiple (both positive and negative) proposed mechanisms of action (Barde et al, 2013;Yang et al, 2013;Pineda et al, 2015), whereas the mechanism of autophagy induction for TRIM13 in response to the ER stress has not been fully delineated (Tomar et al, 2012), although it shows a relationship with p62 and DFCP, an ER-derived autophagy precursor compartment termed omegasome (Axe et al, 2008).…”
Section: Discussionmentioning
confidence: 99%
“…IFN-γ induces autophagy (Inbal et al, 2002;Gutierrez et al, 2004;Fabri et al, 2011) and influences cytokine networks and polarization of immune systems (Ghezzi and Dinarello, 1988;Schroder and Tschopp, 2010;Mishra et al, 2013), whereas TRIMs are involved in immune responses (Kawai and Akira, 2011) and, through an assortment of proposed mechanisms affect autophagy (Niida et al, 2010;Tomar et al, 2012;Barde et al, 2013;Pizon et al, 2013;Yang et al, 2013;Khan et al, 2014;Mandell et al, 2014;Pineda et al, 2015). IFN-γ can induce expression of a subset of TRIMs (Carthagena et al, 2009).…”
Section: Trims Participate In Ifn-γ-induced Autophagymentioning
“…TRIMs affect autophagy as a whole process (Lipinski et al, 2010;Perera et al, 2011;McKnight et al, 2012;Tomar et al, 2012;Barde et al, 2013;Pizon et al, 2013;Khan et al, 2014;Pineda et al, 2015) and interact with ATG factors (Behrends et al, 2010;Yang et al, 2013;Mandell et al, 2014;Kimura et al, 2015). Of the 82 human TRIMs, 49 TRIMs have an effect on autophagy (Table S1).…”
Section: Trims As Autophagy Regulatorsmentioning
confidence: 99%
“…Several genome-wide screens, albeit not aimed at studying TRIMs, indicate that a number of additional TRIMs (TRIM29, TRIM51 and TRIM69) modulate autophagy (Lipinski et al, 2010;McKnight et al, 2012). Furthermore, TRIM13, TRIM28, TRIM55, TRIM56 and TRIM63 have been reported in separate studies to affect autophagy (Tomar et al, 2012;Barde et al, 2013;Pizon et al, 2013;Yang et al, 2013;Khan et al, 2014;Kimura et al, 2015;Pineda et al, 2015).…”
Selective autophagy entails cooperation between target recognition and assembly of the autophagic apparatus. Target recognition is conducted by receptors that often recognize tags, such as ubiquitin and galectins, although examples of selective autophagy independent of these tags are emerging. It is less known how receptors cooperate with the upstream autophagic regulators, beyond the well-characterized association of receptors with Atg8 or its homologs, such as LC3B (encoded by MAP1LC3B), on autophagic membranes. The molecular details of the emerging role in autophagy of the family of proteins called TRIMs shed light on the coordination between cargo recognition and the assembly and activation of the principal autophagy regulators. In their autophagy roles, TRIMs act both as receptors and as platforms ('receptor regulators') for the assembly of the core autophagy regulators, such as ULK1 and Beclin 1 in their activated state. As autophagic receptors, TRIMs can directly recognize endogenous or exogenous targets, obviating a need for intermediary autophagic tags, such as ubiquitin and galectins. The receptor and regulatory features embodied within the same entity allow TRIMs to govern cargo degradation in a highly exact process termed 'precision autophagy'.
“…Pineda et al (2015) reported that the melanoma antigens MAGE-A3/-A6 recruit the ubiquitin ligase TRIM28 to AMPK-α1 and triggers its degradation. MAGE-A3/-A6 are closely related tumour antigens that are normally only expressed in testis, but are aberrantly re-expressed in some tumors.…”
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