Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases.
While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this
phosphate group from ULK1 and promotes the key inducer of autophagosome formation.
However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A. In addition,
the active ULK1 promotes PP2A via phosphorylation. We claim that these double-negative
(mTORC1 –| PP2A –| mTORC1, mTORC1 –| ULK1 –| mTORC1) and positive (ULK1 -> PP2A ->
ULK1) feedback loops are all necessary for the robust, irreversible decision making
process between the autophagy and non-autophagy states. We approach our scientific
analysis from a systems biological perspective by applying both theoretical and molecular
biological techniques. For molecular biological experiments, HEK293T cell line is
used, meanwhile the dynamical features of the regulatory network are described by
mathematical modelling. In our study, we explore the dynamical characteristic of mTORC1-ULK1-PP2A
regulatory triangle in detail supposing that the positive feedback loops are essential
to manage a robust cellular answer upon various cellular stress events (such as mTORC1
inhibition, starvation, PP2A inhibition or ULK1 silencing). We confirm that active
ULK1 can up-regulate PP2A when mTORC1 is inactivated. By using theoretical analysis,
we explain the importance of cellular PP2A level in stress response mechanism. We
proved both experimentally and theoretically that PP2A down-regulation (via addition
of okadaic acid) might generate a periodic repeat of autophagy induction. Understanding
how the regulation of the cell survival occurs with the precise molecular balance
of ULK1-mTORC1-PP2A in autophagy, is highly relevant in several cellular stress-related
diseases (such as neurodegenerative diseases or diabetes) and might help to promote
advanced therapies in the near future, too.
