Rationalizing translation attenuation in the network architecture of the unfolded protein response.
Increased levels of unfolded proteins in the endoplasmic reticulum (ER) of all eukaryotes trigger the unfolded protein response (UPR). Lower eukaryotes solely use an ancient UPR mechanism, whereby they up-regulate ER-resident chaperones and other enzymatic activities to augment protein folding and enhance degradation of misfolded proteins. Metazoans have evolved an additional mechanism through which they attenuate translation of secretory pathway proteins by activating the ER protein kinase PERK. In mammalian professional secretory cells such as insulin-producing pancreatic beta-cells, PERK is highly abundant and crucial for proper functioning of the secretory pathway. Through a modeling approach, we propose explanations for why a translation attenuation (TA) mechanism may be critical for beta-cells, but is less important in nonsecretory cells and unnecessary in lower eukaryotes such as yeast. We compared the performance of a model UPR, both with and without a TA mechanism, by monitoring 2 variables: (i) the maximal increase in ER unfolded proteins during a response, and (ii) the accumulation of chaperones between 2 consecutive pulses of stress. We found that a TA mechanism is important for minimizing these 2 variables when the ER is repeatedly subjected to transient unfolded protein stresses and when it sustains a large flux of secretory pathway proteins which are both conditions encountered physiologically by pancreatic beta-cells. Low expression of PERK in nonsecretory cells, and its absence in yeast, can be rationalized by lower trafficking of secretory proteins through their ERs.
Trusina
Ala
A
California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158, USA.
Papa
Feroz R
FR
Tang
Chao
C
D000818:Animals; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005786:Gene Expression Regulation; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000096:biosynthesis; D014176:Protein Biosynthesis; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D013045:Species Specificity; D015003:Yeasts / Q000378:metabolism; D019892:eIF-2 Kinase
D018832:Molecular Chaperones; D011506:Proteins; D019892:eIF-2 Kinase