Protein helps cells survive or die

In one study, scientists showed how cell stress prevents and promotes cell suicide, both of which are balanced.

July 3 An article published in the journal Science reported that the unfolded protein response (UPR) cell stress pathway not only activates the death receptor 5 protein (DR5) to promote cell suicide, but also inhibits cell suicide by degrading DR5 . The theory suggests that initial stress can impede cell suicide or apoptosis, giving cells the opportunity to adapt, but if this pressure persists, it will eventually trigger apoptosis.

Korennykh, a professor of molecular biology at Princeton University who did not participate in the work, said that " this study is the most simplistic simplification of the extremely complex and chaotic situation. Fundamentally, they identify and accurately identify and transform decisions and decisions. Related to special proteins. "

But this did not impress Randal Kaufman of the Burnham Institute of Medicine in La Jolla, California . He questioned the physiological relevance of this key cellular process experiment in support of the author's main point of view.

Protein folding in one cell occurs mainly in the endoplasmic reticulum, but if this process goes wrong, unfolded protein accumulates, which puts a burden on the endoplasmic reticulum. This triggers the UPR reaction, resulting in a stop of translation, an unfolded protein degradation, and an increased protein folding mechanism product. However, if endoplasmic reticulum stress is not resolved, the UPR response may also trigger apoptosis.

There are two main factors IRE 1a Reacts with UPRK to control UPR . IRE 1a Promote cell survival by activating the transcription factor XBP1 to trigger the expression of cell survival genes. On the other hand, PERK activates another transcription factor, CHOP , which in turn triggers the expression of pre-apoptotic factor DR5 .

The University of California, Peter Walter, and his colleagues have confirmed that CHOP activation of DR5 is a cellular autonomic process. But they have found IRE 1a DR5 inhibiting action, called by IRE-dependent 1a The regulated degradation (RIDD) process directly degrades the mRNA encoding DR5 . Inhibition of IRE in tumor cell lines that have undergone endoplasmic reticulum stress 1a Not only can it prevent the attenuation of DR5 mRNA but also increase apoptosis.

But in an email to The Scientist , Kaufman expressed concern about the importance of the RIDD process not yet being addressed in any of the physiologically relevant literature.

Walter insists that the evidence for the existence of the RIDD process is very clear. His only concession is that the effect of RIDD may not reach 100% , because RIDD degrades mRNA in many ways, which leads to some difficulties in measurement.

In addition to the debate about RIDD , the researchers also triggered another riot, they found that only 24 hours after the endoplasmic reticulum stress response started IRE 1a The expression is turned off, leaving PERK to promote apoptosis. Scott Oakes , a professor of pathology at the University of California, said: " We and other colleagues have evidence that this process reveals another model, PERK and IRE. 1a The death signal will be released under high pressure. ”

Ira Tabas , a professor at Columbia University , said that regardless of IRE 1a It is controversial to promote or inhibit apoptosis under extreme stress. But scientists can figure out this is very important. Tabas said that cell death under ER stress is a pathological process of many major diseases, IRE 1a Inhibitors can be used in drug discovery. Oakes said that it is very important that you hold two different opinions under high stress. One is that you want to keep IRE. 1a Open, the other is that you want to turn it off.

Because ER stress is very important for many diseases, " many people are keen on it . " Tabas explains: “ Who is right? I think it depends on the situation in which the experiment is done – one approach may be important in some cases, and the other approach may be important in different situations. ” He also said In vivo studies using actual disease models may help resolve these issues in the future.

Walter said that researchers will continue to debate this issue, and which views will prevail in the next five years, we will wait and see.

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