When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen
Figure 1
Pathways of autophagy induction by hypoxia. During hypoxia, autophagy is activated by sensors that detect low oxygen, unfolded proteins, and energy depletion. Low O2: in the absence of oxygen, the alpha subunit of the transcription factor HIF-1 is stabilized resulting in the expression of the regulatory proteins BNIP3 and BNIP3L. BNIP3 and BNIP3L interact with Bcl-2 and Bcl-xL proteins that inhibit Beclin1, a key regulator of autophagy induction. The resulting liberation of Beclin1 leads to the activation of autophagy [8]. (BNIP3L and Bcl-xL are not shown in the figure). Unfolded Protein Response: autophagy may be induced during hypoxia as a result of signals generated by the unfolded protein response in the endoplasmic reticulum. PERK detects unfolded proteins and induces ATF4 to upregulate the expression of the essential autophagy genes LC3 and ATG5 [28, 29, 33]. LC3 I is processed to its active form, LC3 II, and trafficked with the ATG5-ATG12-ATG16 complex to the elongating autophagosome. Energy Depletion: increases in the intracellular ratio of AMP to ATP during hypoxia activates AMPK, an energy sensing switch that activates autophagy both directly and indirectly by inhibiting mTOR [14, 101].
