Regulatory crosstalk within the mammalian unfolded protein response

Increased demands on the protein folding capacity of the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR). Comprised of a tripartite signaling system, the UPR regulates translation and gene transcription to manifest pro-adaptive and, if necessary, pro-apoptotic outcomes. The three UPR pathways, initiated by activating transcription factor 6, inositol requiring enzyme 1, and protein kinase RNA-activated-like ER kinase (PERK), direct distinct downstream signaling events. However, it is becoming increasingly clear that interplay between the cascades is vital in shaping the UPR. In particular, recent discoveries have revealed that PERK-dependent signals mediate both inter- and intra-pathway regulation within the UPR, underscoring the critical role of the PERK pathway in the cellular response to ER stress.