The Endoplasmic Reticulum: Crossroads for Newly Synthesized Polypeptide Chains

About one third of the proteins synthesized in mammalian cells are cotranslationally translocated in the endoplasmic reticulum (ER). Newly synthesized polypeptides emerging in the ER lumen are exposed to machineries that assist conformational maturation and to machineries designed to interrupt futile folding attempts and to destroy terminally misfolded proteins. Cell and organism homeostasis depends on the regulated balance between these two activities. In this review, we summarize recent progresses made in the characterization of protein folding, quality control, and degradation in the mammalian ER; we survey the literature on the several knockouts of ER-resident proteins made available in recent years; we compare conflicting models explaining how these processes are regulated in yeast and in mammalian cells; we eventually propose the existence of regulatory mechanisms named ERAD tuning that operate at steady state in mammalian cells to optimize protein biogenesis and rely oil the selective segregation from the folding environment and destruction of ER-resident regulators of protein disposal.