ULK1 - mammalian homologue of the yeast ATG1 kinase

Wed, 08/26/2015 - 15:09

Autophagy is an important cellular process involved in degradation and recycling of cellular macromolecules in response to stress or starvation. Autophagy is carried out in four main phases: phagophore nucleation, autophagosome elongation, docking and fusion with a lysosome, and vesicle breakdown and degradation. ULK1, also known as UNC51-like autophagy activating kinase 1, is a 112 kDa protein with serine-threonine kinase activity. ULK1 is one of two mammalian homologues of the yeast ATG1 kinase, known for its role in autophagy initiation (1). ULK1 forms a complex with ATG13 and FIP200 which is activated by mTORC1 and AMPK in the setting of nutrient and energy deprivation (2). Active ULK1 subsequently phosphorylates Beclin-1, which induces the autophagic activity of VPS34 complexes bound to ATG14L via PI3P. VPS34 is a mammalian class III PI3K known to induce autophagy and promote phagophore maturation into a double-membraned autophagosome. ULK1 also phosphorylates AMPK in a negative feedback loop to terminate autophagic signaling. ULK1 has been suggested to interact with many other autophagy proteins.  

Lu et. al. used the ULK1 antibody to study autophagy in the setting of ovarian cancer (3). The group sought to characterize the tumor suppressor gene DIRAS3 and its role in autophagy initiation. They used the ULK1 antibody to look at levels of ULK1 in ovarian cancer cell lines with an siRNA knockdown of DIRAS3. The ULK1 antibody showed no difference in levels of ULK1 in the controls and knockdowns. Interestingly, DIRAS3 knockdowns significantly impaired the accumulation of Beclin-1 and ATG14, suggesting a role in the formation of the Beclin-1/ATG14 complex downstream of ULK1.

Yang et. al. sought to understand how Chloroquine, a pharmacologic autophagy inhibitor, inhibits inflammatory signaling in the setting of sepsis (4). They found that Chloroquine inhibits HMGB1 inflammatory signaling and limits sepsis mortality in mice. Given Chloroquine’s role as an autophagy inhibitor, the group used the ULK1 antibody to try to tease apart the mechanism behind Chloroquine’s anti-inflammatory activity. They used shRNA knockdown against ULK1 and confirmed via western blot with the ULK1 antibody. The group found that either Chloroquine or shRNA knockdown of ULK1 or Beclin-1 inhibited HMGB1 activity, ultimately preventing NFκB-mediated release of TNF and IL-6 cytokines. Given the differences in human and murine inflammatory signaling, the group suggests the need to further explore this pathway in humans.


  1. 23685627
  2. 21460634
  3. 24879154
  4. 23707973

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