University of Michigan researchers have discovered a novel energy sensor in the Golgi, an essential cellular structure that serves as the “post office” and “sugar factory” of the cell. As the “sugar factory,” the Golgi has many enzymes that add sugars and other modifiers to proteins and lipids, and thereby affects their structure, function and stability, explains Yanzhuang Wang, professor of molecular, cellular and developmental biology, and principal investigator of the research group that made the discovery. As the “post office” the Golgi send proteins to the right place inside and outside of the cell where they perform their functions. Golgi function is essential for normal functioning yet little is known about how the Golgi responds to cellular stresses such as energy deprivation. This discovery, just published in Developmental Cell, helps decode the molecular mechanism that controls Golgi stress response. It also contributes to the understanding of human diseases related to Golgi dysfunction.

Depending on the energy available, many proteins in the cell cytoplasm are modified by the addition or removal of N-acetylglucosamine, called O-GlcNAcylation. This process is usually controlled by glucose. To find the energy sensor in the Golgi, the UM researchers analyzed
a number of Golgi structural proteins. They found that a protein called GRASP55 is modified by O-GlcNAc. Subsequently, they showed that GRASP55 O-GlcNAcylation is enhanced when glucose is high and is reduced when glucose is low.

Microscopic images of cells incubated in growth medium (A) or glucose starvation medium (B-C) and stained for GRASP55 (green) and LC3 (Red). (C) shows a zoom-in image of the indicated frame in (B). Note that GRASP55 is only located in the Golgi (indicated by asterisks) under growth condition, and is targeted to LC3 positive autophagosomes (arrows). Scale bar, 20 µm in (A-B) and 4 µm in (C).

In addition to its important function, the Golgi has perhaps the most beautiful membrane architecture in the cell, says Wang. Its basic structure is 5 to 6 flat membrane discs that are closely aligned into a stack, like you overlay a number of pancakes into a stack. Previously, this group has identified GRASP55, and its homologue protein GRASP65, as the glue that holds the flat membrane discs together to form this multilayer structure. Removing these gluing proteins disrupts the Golgi structure, affecting protein sugar modification and protein trafficking. Golgi defects may also contribute to the development of diseases. Previously, the same group has reviewed the mechanism how the Golgi structure becomes fragmented in Alzheimer's patients.

“It is logical to expect that GRASP55 O-GlcNAcylation will affect Golgi structure and function. However, it is surprising to see that upon energy deprivation, de-O-GlcNAcylated GRASP55 is targeted to autophagasomes and regulates autophagosome maturation,” explains Wang.

Autophagy is a stress response from cells when they have a low supply of energy and nutrients. Under these conditions, cells form a double membrane structure inside the cell to wrap un-used membranes or proteins, called autophagosomes. Later on, autophagosomes fuse with another membrane structure called lysosomes, the recycle bins in the cell. The fusion of autophagosome with lysosome allows the degradation of proteins. This generates building materials and energy sources for the cells to reuse.

This finding is significant as it not only links different membrane structures, but also revealed a new mechanism on how cells respond to energy deprivations, similar situations can be found in many diseases, says Wang.

This research is funded by the National Institutes of Health.  Xiaoyan Zhang, a research fellow in Wang's lab, is the lead author of the Developmental Cell paper.


GRASP55 Senses Glucose Deprivation through O-GlcNAcylation to Promote Autophagosome-Lysosome Fusion

Developmental Cell
Volume 45, Issue 2, p245–261.e6, 23 April 2018



Wang Lab