Abstract
Cellular homeostasis is controlled by an evolutionary conserved cellular digestive process called autophagy. This mechanism is tightly regulated by the two sensor elements called mTORC1 and AMPK. mTORC1 is one of the master regulators of proteostasis, while AMPK maintains cellular energy homeostasis. AMPK is able to promote autophagy by phosphorylating ULK1, the key inducer of autophagosome formation, while mTORC1 downregulates the self-eating process via ULK1 under nutrient rich conditions. We claim that the feedback loops of the AMPK–mTORC1–ULK1 regulatory triangle guarantee the appropriate response mechanism when nutrient and/or energy supply changes. In our opinion, there is an essential double negative feedback loop between mTORC1 and AMPK. Namely, not only does AMPK downregulate mTORC1, but mTORC1 also inhibits AMPK and this inhibition is required to keep AMPK inactive at physiological conditions. The aim of the present study was to explore the dynamical characteristic of AMPK regulation upon various cellular stress events. We approached our scientific analysis from a systems biology perspective by incorporating both theoretical and molecular biological techniques. In this study, we confirmed that AMPK is essential to promote autophagy, but is not sufficient to maintain it. AMPK activation is followed by ULK1 induction, where protein has a key role in keeping autophagy active. ULK1-controlled autophagy is always preceded by AMPK activation. With both ULK1 depletion and mTORC1 hyper-activation (i.e., TSC1/2 downregulation), we demonstrate that a double negative feedback loop between AMPK and mTORC1 is crucial for the proper dynamic features of the control network. Our computer simulations have further proved the dynamical characteristic of AMPK–mTORC1–ULK1 controlled cellular nutrient sensing.
Highlights
The maintenance of cellular homeostasis against external and internal stimuli is controlled by complex protein–protein regulatory pathways
Szymanska et al built a mathematical model based on the mTOR–AMPK–ULK1 regulatory triangle to explain cellular autophagy induction upon rapamycin treatment or glucose starvation [33]
To further confirm the effect of ULK1 silencing on autophagy induction, the expression of ULK1 siRNA was followed by rapamycin treatment (100 nM, 2h) or starvation (i.e., AMPK hyper-activation)
Summary
The maintenance of cellular homeostasis against external and internal stimuli (such as starvation, inflammatory mediators) is controlled by complex protein–protein regulatory pathways. 6].quickly blocks the anabolic processes of the cell [2,3] This mechanism is tightly regulated by the two mTOR issenmasoTrOseRrleinmeise/tnhtarseosfnenirniuneter/iptehnrrotetcoeoinnindeiktionpnarsoetaeniandnednkienirsagsyetshueapnpdmlya:insontechooemf tpmhoeanimennTtOcoRomf(pmmoanTmeOnmtRaloiafn mtaTrgOeRt of pathway-regpuartlahaptweadamyyc-receilnlgu)ulclaaortmepdprolcetexeleolsustlaansrdispArboMytePionKstte(aAgsriMsatPibnyagcitdnivitfeafgteerdaetnpintrgostiegdininfafklesirnesanustceh)sikgainnsaalgsseros[w4u–ct6h].afasctgorrosw, th factors, amino acidasm, ginluocmoascTeiOd, sRa,nisgdalusecenoresinrege, y/tahnsrdteaotneunisneertgopyroctosetnianttrukosilnatgosreocwaontndhtrisoatlnhdgermmowaeitnahcbooamlnisdpmonme[e7nt,ta8ob].fomlFisoTmrORp[r7po,a8pt]eh. AMPK[1is3g]al.yhAceoMtleyPrsoiKst,riiβsm-aoehxriecdteaprtrioottnrei)imn[1ec1ro,i1cm2p]prbloeytxesiaennndcsoinimtgipselnfeaexirraglnydsleivtnesislistfitavoiermltyoastienhnteascinthivacnelgtloue litanhrethhcoehmacneloglsuetlaiansristh[e13c]e.lAluMlarPK AMP/ATP rAatMiisoP.a/WAhehTtePnrroatthtrieom.AeWMrihcPepnlerovthteeeliniAs cMhoiPmghlpeilvneextlhaiesndhceiigltlh,istihnfeatifhrrleeyecseAelnlM,stiPhtievdefirteoecttAlhyMebcPinhdansirgetoectiAlnyMtbhPineKdcsealntloudlAarMAPMKPa/nAdTP turns it on [t2u].ranAtsiMoit.PoWKnhb[e2en]c.otAhmeMeAsPMaKcPtbivelecevowemlheiessnhaicgttihvsiepnwhtohhseepncheioltlr,iysthlpaethefodresepathAtohMreyPlTadhteirrd-e1ca7tt2lytrhbeesiniTddhusre-t1o[71A24]Mr.ePsiKduaned[1t4u]r.ns it on [2]. Acteristics of the AMPK–mTORC1–ULK1 regulatory triangle, a computational analysis was performed by Szymanska et al [33] Their mathematical model was formulated to study the systems-level consequences of interactions among AMPK, mTORC1, and ULK1 by mainly focusing on autophagy induction upon various stress events [33]. Rreessuplotsnd torceeslpluolnadr sttorecseslleuvlaernststr[e1s3s,3e2v]e.nts [13,32]
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