TMEM2 Modulates ER Stress in a Non-canonical Manner
Authors: Renata L.S. Goncalves, Gökhan S. Hotamisligil
Journal: Cell Metabolism (2019)

Cells utilize multiple mechanisms to support endoplasmic reticulum (ER) function. The unfolded protein response, UPRER, is engaged during proteotoxic challenges to either mitigate ER stress or promote apoptosis. In a CRISPR-based genetic screen, Schinzel et al., 2019Schinzel R.T. Higuchi-Sanabria R. Shalem O. Moehle E.A. Webster B.M. Joe L. Bar-Ziv R. Frankino P.A. Durieux J. Pender C. et al.The hyaluronidase, TMEM2, promotes ER homeostasis and longevity independent of the UPRER.Cell. 2019; 179: 1306-1318Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar identified TMEM2 as a mediator of ER stress tolerance independent of the individual branches of the canonical UPRER and linked this path to nematode longevity. Cells utilize multiple mechanisms to support endoplasmic reticulum (ER) function. The unfolded protein response, UPRER, is engaged during proteotoxic challenges to either mitigate ER stress or promote apoptosis. In a CRISPR-based genetic screen, Schinzel et al., 2019Schinzel R.T. Higuchi-Sanabria R. Shalem O. Moehle E.A. Webster B.M. Joe L. Bar-Ziv R. Frankino P.A. Durieux J. Pender C. et al.The hyaluronidase, TMEM2, promotes ER homeostasis and longevity independent of the UPRER.Cell. 2019; 179: 1306-1318Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar identified TMEM2 as a mediator of ER stress tolerance independent of the individual branches of the canonical UPRER and linked this path to nematode longevity. The endoplasmic reticulum (ER) is a highly dynamic, multi-domain, intricate, and vast network of tubules and sheets that spread throughout the cytosol and is responsible for a plethora of functions including calcium storage, cell survival, immune response, and metabolic regulation. Approximately 50% of proteins are synthesized, matured, and targeted for secretion in the ER, which requires an effective quality control system to assure that proteins are properly folded, sending the misfolded/unfolded proteins for degradation. As such, ER adaptive responses are tightly coupled to protein disposal machineries of the cell. Despite the presence of multiple checkpoints, ER function can be challenged under different physiological or pathological conditions (Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar). To protect ER integrity and respond to these insults, cells have evolved sophisticated adaptive response systems to preserve ER homeostasis including the unfolded protein response (UPRER) and autophagy (Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar). The UPRER monitors the ER lumen folding capacity through three ER-membrane embedded proteins, ATF6 (activating transcription factor-6), PERK (PKR-like eukaryotic initiation factor 2α kinase/EIF2AK3), and IRE1 (inositol requiring enzyme 1). For example, the endonuclease activity of IRE-1 cleaves and activates the transcriptional factor XBP-1, launching one of the pathways to expand ER folding capacity. On the other hand, activated PERK halts protein synthesis and induces genes related to apoptosis and redox control (Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar). The signaling cascade activated by these sensors supports proteostasis and fine-tunes the UPRER threshold for protein overload and apoptosis (Ron and Walter, 2007Ron D. Walter P. Signal integration in the endoplasmic reticulum unfolded protein response.Nat. Rev. Mol. Cell Biol. 2007; 8: 519-529Crossref PubMed Scopus (4863) Google Scholar), which is critical for proper immune system activation and tumorigenesis. Interestingly, UPRER functionality declines during aging (Frakes and Dillin, 2017Frakes A.E. Dillin A. The UPRER: sensor and coordinator of organismal homeostasis.Mol. Cell. 2017; 66: 761-771Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar), while in obesity it is maintained in a dysregulated manner and contributes to metabolic deterioration (Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar). In a new study, Schinzel et al., 2019Schinzel R.T. Higuchi-Sanabria R. Shalem O. Moehle E.A. Webster B.M. Joe L. Bar-Ziv R. Frankino P.A. Durieux J. Pender C. et al.The hyaluronidase, TMEM2, promotes ER homeostasis and longevity independent of the UPRER.Cell. 2019; 179: 1306-1318Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar performed a whole-genome CRISPR knockout screen using human immortalized fibroblasts to gain further insight into ER stress management. They identified the hyaluronidase TMEM2 as an ER stress modulator acting outside of the ER to improve cell survival (Figure 1). In an elegant and unbiased manner, Schinzel et al. showed that TMEM2 changes the EC50 of chronic tunicamycin exposure and, therefore, modulates ER stress sensitivity. The authors demonstrated that while TMEM2-deficient cells had increased sensitivity to ER stress, cells overexpressing TMEM2 had improved cell survival. TMEM2 degrades the glycosaminoglycan hyaluronan (HA) into low molecular weight HA, which is necessary and sufficient to improve cell survival in the presence of tunicamycin. Notably, this mechanism seems to be independent of the canonical UPRER branches, as inhibition or knocking out of IRE1, PERK, or ATF6 individually fails to alter the sensitivity of TMEM2-deficient cells to tunicamycin. ER stress and UPRER signaling intersect with different families of inflammatory and stress signaling cascades including p38, ERK, JNK, IKK, and inflammasome components. The signaling outcomes through these complex systems are highly dependent on the cell type, context, and most critically, engagement of specific isoforms. For example, the p38 family is composed of four isoforms in mammals (p38α, p38β, p38γ, and p38δ) and three in C. elegans (PMK 1–3). While some overlap may exist, recent genetic and functional studies highlighted the distinct biology of each isoform. As examples, p38γ and p38δ are increased and exert detrimental effects in obesity and fatty liver disease (González-Terán et al., 2016González-Terán B. Matesanz N. Nikolic I. Verdugo M.A. Sreeramkumar V. Hernández-Cosido L. Mora A. Crainiciuc G. Sáiz M.L. Bernardo E. et al.p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration.EMBO J. 2016; 35: 536-552Crossref PubMed Scopus (45) Google Scholar), while p38α was found to block brown adipose tissue thermogenesis through p38δ inhibition (Matesanz et al., 2018Matesanz N. Nikolic I. Leiva M. Pulgarín-Alfaro M. Santamans A.M. Bernardo E. Mora A. Herrera-Melle L. Rodríguez E. Beiroa D. et al.p38α blocks brown adipose tissue thermogenesis through p38δ inhibition.PLoS Biol. 2018; 16: e2004455Crossref PubMed Scopus (23) Google Scholar). Identification of the isoforms involved in TMEM2 function may help elucidate the results described here, where the lack of p38 in human fibroblasts has the same effects on cell proliferation in TMEM2-deficient and overexpressing cells. As impaired ER function and proteostasis are implicated in aging and associated disorders, mechanisms that allow better stress management may impact these parameters. To test this, Schinzel et al. introduced human TMEM2 (hTMEM2) in C. elegans and showed that hTMEM2 overexpression increased lifespan. They also presented data supporting improved ER folding capacity during aging using the hsp-4p:GFP transcriptional reporter assay. In agreement with the results obtained with human fibroblasts, the beneficial effects of hTMEM2 are independent of the individual UPRER branches, ire-1/xbp-1, atf-6, and pek-1 (PERK homolog). Schinzel et al. also showed that suppression of pmk-1 and mpk-1 (p38 and ERK homologs) abrogated hTMEM2 effects on longevity. Whether this response is transmitted through one or more forms of these kinases is not clear, and further research is necessary to define the function of each p38 and ERK isoform on folding capacity and longevity. The biological function of HA depends on its molecular size. An exceptional example is the naked mole rat, the longest living rodent, which expresses ultra-high molecular weight HA exerting potent oncoprotective functions (Tian et al., 2013Tian X. Azpurua J. Hine C. Vaidya A. Myakishev-Rempel M. Ablaeva J. Mao Z. Nevo E. Gorbunova V. Seluanov A. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.Nature. 2013; 499: 346-349Crossref PubMed Scopus (499) Google Scholar). The study by Schinzel et al. highlights the importance of extracellular matrix components to cell signaling and proposes a mechanism that may link these mediators to aging (Figure 1). A key insight from this work is that the traditional three-armed UPRER may not be complete and non-canonical systems exist to mitigate ER stress (Hotamisligil, 2010Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.Cell. 2010; 140: 900-917Abstract Full Text Full Text PDF PubMed Scopus (2090) Google Scholar). The regulation of protein degradation is emerging as a critical process to aid ER homeostasis, especially under challenging conditions. Nfe2l1 (also known as Nrf1), for example, is an ER-localized transcription factor, which is necessary for regulating proteasome activity in metabolic context and protecting ER function in adipose tissue and acts outside the canonical UPR (Bartelt et al., 2018Bartelt A. Widenmaier S.B. Schlein C. Johann K. Goncalves R.L.S. Eguchi K. Fischer A.W. Parlakgül G. Snyder N.A. Nguyen T.B. et al.Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.Nat. Med. 2018; 24: 292-303Crossref PubMed Scopus (109) Google Scholar). It is tempting to consider a potential link between TMEM2/HA axis and other systems that operate independently of the classical UPR such as Nrf1 and LRH-1/nr5a2 (Mamrosh et al., 2014Mamrosh J.L. Lee J.M. Wagner M. Stambrook P.J. Whitby R.J. Sifers R.N. Wu S.P. Tsai M.J. Demayo F.J. Moore D.D. Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution.eLife. 2014; 3: e01694Crossref PubMed Google Scholar). Future experiments to explore the mechanisms by which TMEM2/HA modulates ER stress sensitivity and whether other mechanisms can compensate for the absence of more than a single UPRER pathway would be informative. For example, can TMEM2 overexpression rescue tunicamycin sensitivity or longevity when multiple branches of the UPRER are deleted simultaneously? The mechanisms in place to assure survival and homeostasis fall into two categories: clearance of stress, leading to resistance, or reduced impact of the stress, leading to tolerance (Torres et al., 2016Torres B.Y. Oliveira J.H.M. Thomas Tate A. Rath P. Cumnock K. Schneider D.S. Tracking resilience to infections by mapping disease space.PLoS Biol. 2016; 14: e1002436Crossref PubMed Scopus (72) Google Scholar). Increased ER folding capacity when UPRER is activated decreases misfolded proteins, promoting ER stress resistance. It would be interesting to explore if TMEM2/HA improves ER folding capacity (resistance) or limits the damage in response to ER stress (tolerance). Also, it will be important to explore whether the role of TMEM2/HA in survival and longevity is universal to other forms of ER stress and other pathologies that have been linked to dysfunction of the ER such as cancer and metabolic disease. R.L.S.G. is supported by the Bart Syndrome Foundation and Sabri Ülker Center, and G.S.H. is supported by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health, USA. The authors declare no competing interests related to the contents of this paper. G.S.H. is in the Scientific Advisory Boards of Seven Bridges Corporation and Crescenta Pharmaceuticals, in areas not related to the contents of this paper. The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRERSchinzel et al.CellNovember 21, 2019In BriefIntracellular ER stress resistance is impacted by changes in extracellular matrix metabolism. Full-Text PDF Open Archive