The Communication of Endoplasmic Reticulum Stress

The endoplasmic reticulum (ER) is responsible for the folding and maturation of up to as many as 13 million proteins per minute. Challenges to the ER folding environment can have a multitude of consequences on an organism’s viability: defects in ER function are strongly associated with a large number of metabolic and age-onset disorders. Upon ER stress, the unfolded protein response of the ER (UPRER) is activated to restore homeostasis. In one line of work, we screened for novel regulators of protein homeostasis in the ER, and found that the cell-membrane Hyaluronidase, TMEM2, positively regulates ER proteostasis (1). We also recently uncovered a communication between lysosomes and the UPRER. We are currently working towards elucidating the mechanistic details of these interactions of the ER with other cellular components, and their conservation in mammalian systems. 

 

While it was previously believed that UPRER is regulated in a cell autonomous fashion, our laboratory discovered that neurons are able to sense ER stress and induce UPRER in peripheral tissues. More specifically, ectopic expression of the UPRER transcription factor, xbp-1s, in neurons leads to cell non-autonomous activation of the UPRER in distal, intestinal cells in C. elegans (2). This transcellular signaling is sufficient to prevent age-onset loss of UPRER, confer stress resistance, and prolong lifespan, with lipophagy playing a major role in providing these beneficial effects (3). Initially, this phenomenon was only ascribed to neurons. However, we identified a specific subset of glial cells that are central participants in coordinating systemic protein homeostasis and aging through a completely distinct mechanism. We wish to identify the upstream cues which induce neuronal or glial XBP1s, how these signals are perceived across the organism during aging, and the extent to which this signaling is conserved in mammals (4). 

​

(1) Schinzel RT, Higuchi-Sanabria R, et al. 

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER

Cell. 2019.  PMID  31761535 

​

​

(2) Taylor RC et al.

XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity.

Cell. 2013.   PMID 23791175 

​

​

(3) Daniele JR, Higuchi-Sanabria R, et al.  

UPRER promotes lipophagy independent of chaperones

to extend life span. 

Science Advances.  2020.  PMID 31911951

​

​

(4) Frakes AE et al. 

Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans. 

Science.  2020.   PMID 31974253