Starvation Regulates Ubiquitin-like Modifiers Critical for Stress Responses — ASN Events
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  3. Starvation Regulates Ubiquitin-like Modifiers Critical for Stress Responses

Starvation Regulates Ubiquitin-like Modifiers Critical for Stress Responses (#010)

Mark Larance 1 , Angus I Lamond 1
  1. Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom

We have shown previously that nutrient deprivation in the model animal C. elegans will alter signalling pathways that control longevity1. These responses are known to be regulated by protein-protein interactions, but such changes are largely uncharacterised. To identify the pathways regulated during mammalian starvation responses, we have used proteome-wide analysis of protein abundance and interactions in mouse tissues. We analysed liver, white adipose tissue, spleen and skeletal muscle after starvation (16 hours), compared to animals fed ad libitum. This label-free analysis allowed quantitation of >6000 proteins, the most comprehensive thus far.

One of the most surprising findings was the decreased abundance of the ubiquitin-like protein UFM1. The total abundance of UFM1 (including conjugated and unconjugated forms) was significantly (P<0.000015) decreased more than 2-fold in starved mouse liver. Other proteins in the UFM1-conjugation pathway were not significantly changed in abundance. Quantitative immunoblotting pinpointed the UFM1-UFC1 (E2) conjugate as significantly decreased in abundance in starved mouse liver. In addition, we were able to identify novel direct substrates of UFM1 conjugation involved in liver metabolism, using high resolution tandem MS analysis. We hypothesise that UFM1-conjugation is detrimental to their activity.

Previously, we developed a workflow for the analysis of native protein-protein interactions using protein correlation profiling2. We have now applied this method to analyse the starvation response in liver.  These data show, for the first time, protein complex regulation is significant among the ~4000 proteins analysed, even in the absence of protein abundance changes. We observed a significant decrease in the interaction of UFM1 and its corresponding E1 (UBA5) and E2 (UFC1) enzymes after starvation. Like the UFM1 immunoblotting, this suggests a significant reduction in UFM1 pathway activation in response to starvation stress. Interestingly, UFM1 has previously been shown to have a role in stress responses such as ER stress and oxidative stress. Our finding that starvation regulates this pathway and UFM1-target proteins has provided new mechanistic insight into the nutrient deprivation response.

  1. Larance M, Pourkarimi E, Wang B, Brenes Murillo A, Kent R, Lamond AI, Gartner A. (2015). Global Proteomics Analysis of the Response to Starvation in C. elegans. Mol. Cell. Proteomics. 14(7):1989-2001.
  2. Kirkwood KJ, Ahmad Y, Larance M, Lamond AI. (2013). Characterization of native protein complexes and protein isoform variation using size-fractionation-based quantitative proteomics. Mol. Cell. Proteomics. 12(12):3851-3873.