Schröder M, Chang J S, Kaufman R J
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0650, USA.
Genes Dev. 2000 Dec 1;14(23):2962-75. doi: 10.1101/gad.852300.
Diploid budding yeast exhibits two developmental programs in response to nitrogen starvation, pseudohyphal growth, and sporulation. Here we show that both programs are repressed by activation of the unfolded protein response (UPR), a stress-signal transduction pathway responsible for induction of endoplasmic reticulum (ER)-resident chaperones when protein folding in the ER is impaired. Pseudohyphal growth was derepressed in ire1Delta/ire1Delta and hac1Delta/hac1Delta strains. Activation of the UPR or overexpression of the transcription factor Hac1(i)p, the product of an unconventional splicing reaction regulated by the UPR, was sufficient for repression of pseudohyphal growth and meiosis. HAC1 splicing occurred in a nitrogen-rich environment but ceased rapidly on nitrogen starvation. Further, addition of ammonium salts to nitrogen-starved cells was sufficient to rapidly reactivate HAC1 splicing. We propose that high translation rates in a nitrogen-rich environment are coupled to limited protein unfolding in the ER, thereby activating the UPR. An activated UPR then represses pseudohyphal growth and meiosis. Nitrogen starvation slows translation rates, allowing for more efficient folding of nascent polypeptide chains, down-regulation of the UPR, and subsequent derepression of pseudohyphal growth and meiosis. These findings significantly broaden the range of physiological functions of the UPR and define a role for the UPR in nitrogen sensing.
二倍体出芽酵母在应对氮饥饿、假菌丝生长和孢子形成时会展现出两种发育程序。在此我们表明，这两种程序均会因未折叠蛋白反应（UPR）的激活而受到抑制，UPR是一种应激信号转导途径，当内质网（ER）中的蛋白质折叠受损时，它负责诱导内质网驻留伴侣蛋白。在ire1Delta/ire1Delta和hac1Delta/hac1Delta菌株中，假菌丝生长的抑制被解除。UPR的激活或转录因子Hac1(i)p（一种由UPR调节的非常规剪接反应的产物）的过表达足以抑制假菌丝生长和减数分裂。HAC1剪接在富氮环境中发生，但在氮饥饿时迅速停止。此外，向氮饥饿细胞中添加铵盐足以迅速重新激活HAC1剪接。我们提出，富氮环境中的高翻译速率与内质网中有限的蛋白质解折叠相关联，从而激活UPR。激活的UPR随后抑制假菌丝生长和减数分裂。氮饥饿会减缓翻译速率，使新生多肽链能更有效地折叠，下调UPR，并随后解除对假菌丝生长和减数分裂的抑制。这些发现显著拓宽了UPR的生理功能范围，并确定了UPR在氮感知中的作用。
