A Research Blog

Human GADD34 (Image credit Phosphositeplus, www.phosphosite.org)

Image credit: PhosphoSitePlus®, www.phosphosite.org

Name: GADD34-containing eukaryotic initiation factor 2α phosphatase (GADD34)

Action: Dephosphorylates eukaryotic initiation factor 2α (eIF2α), thereby reducing the translation of endoplasmic reticulum (ER)-targeted proteins

Gene: Ppp1r15a

What was known before:

GADD34 was thought to only be expressed as a response to cellular stress, where its main function is to reverse eIF2α phosphorylation and promote the translation of stress response proteins, so as to mitigate cellular stress and facilitate recovery.

What we know now:

NEW! GADD34 is expressed basally, even in times without stress.

NEW! GADD34 facilitates the translation of secretory and membrane-bound proteins at the ER, e.g. insulin-like growth factor binding protein.

NEW! At the start of UPR, basal expression of GADD34 is essential to permit protein synthesis by dephosphorylating eIF2α, and initiate the rapid expression of more GADD34.

NEW! GADD34 facilitates for the UPR translational programme of stress response proteins such as expression of ATF4 and CHOP.

NEW! GADD34 restores protein production by returning ER-bound polysomes to the ER, following their release into the cytosol in early UPR.

The Unfolded Protein Response (UPR)

During times of cellular stress, unfolded proteins accumulate in the cytosol and initiate UPR.

To channel resources towards overcoming cellular stress, UPR effects include the phosphorylation of eIF2α, the enhanced translation of GADD34, as well as the release of ER-bound polysomes into the cytosol.

The significance:

This study adds to our current understanding of the role of GADD34 in the cell both basally and in times of stress. We also glean greater insights into the possible beneficial and detrimental effects of treatments targeting GADD34.

What is this paper:
Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response

Where published:
Molecular and Cellular Biology

Who published:
First author – David W. Reid
Senior author – Shirish Shenolikar

Where are the authors from:
Signature Research Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School

Funding information:
This research was supported by the Duke/Duke-NUS Collaborative Award (Ministry of Health), HHS|National Institutes of Health (GM101533), MOH|National Medical Research Council (NMRC/GMS/1252/2010), NRF| (TCR Flagship Programme administered by MOH NMRC, NMRC/TCR/013-NNI/2014) and the Agency for Science, Technology and Research graduate scholarship.

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