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Entry into the Endoplasmic Reticulum
All biological processes are under regulatory control to provide flexibility to the cell in adapting to changing environmental conditions and cellular demands. A common theme in regulatory systems is the embellishment of a constitutive core machinery with accessory factors that can selectively stimulate or inhibit specific reactions as dictated by cellular need. Even basic cellular events that were once thought to occur constitutively (such as translation and degradation) are highly regulated. It is therefore reasonable to expect the entry (i.e. translocation) of secretory and membrane proteins into the ER to be similarly controlled. But how does this occur? What are the regulatory factors involved? Under what circumstances is translocation regulated? And what happens when translocation is not regulated properly?
By addressing these questions, our laboratory is developing the concept of translocational regulation and defining roles for this type of cellular control in both normal physiology and disease pathogenesis. An important advance in this area was our discovery that protein translocation into the ER is regulated during acute ER stress. The principal purpose of stress-dependent translocational regulation is to protect cells from excessive protein misfolding in the ER. This ‘pre-emptive’ quality control (pQC) pathway selectively attenuates the import of some, but not all substrates in a signal sequence-dependent manner (see Figure). The pQC pathway therefore represents the first example of translocational regulation and provides us with a useful model system to explore its mechanistic basis.
