Eric (VJ) Rubenstein
Professor of Biology
Yale University, Postdoctoral Fellowship (2008 - 2012)
University of Pittsburgh School of Medicine, PhD (2003 - 2008)
Grove City College, BS (1998 - 2002)
The loss of regulated protein degradation is involved in the pathogenesis of many human diseases, including cancer, neurodegenerative conditions, cystic fibrosis, and cholesterol-related pathologies. Misfolded and potentially harmful proteins that accumulate at the endoplasmic reticulum (ER) are degraded via one of several forms of protein quality control. For poorly characterized reasons, endomembrane system and secretory proteins may stall in the ER translocon (the primary channel responsible for moving proteins across the ER membrane). Cells employ multiple protein quality control mechanisms to recognize and destroy translocon-clogging proteins. In this way, the clogged translocon may resume its function in transporting other proteins across the ER membrane.
We have identified one such mechanism for the destruction of proteins that persistently or aberrantly engage the ER translocon, termed ERAD-T (ER-Associated Degradation of Translocon-clogging proteins). ERAD-T is mediated by the Hrd1 ubiquitin ligase but differs fundamentally from other characterized Hrd1-dependent ERAD pathways. Mammalian apolipoprotein B (a component of low-density lipoproteins, LDL, i.e. “bad cholesterol”) is also targeted for degradation by Hrd1 when its translocation into the ER has stalled (e.g. following pharmacologic intervention). A long-term goal of our laboratory is to understand the mechanism of ERAD-T using budding yeast (Saccharomyces cerevisiae) as a model organism. Such an improved understanding may inform the development of improved therapeutic strategies for cholesterol-related (and potentially other) pathologies.
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(Mentored student co-authors italized)
Broshar CL, Rubenstein EM (2020). Glucose concentration does not affect degradation of a protein that aberrantly engages the endoplasmic reticulum translocon. microPublication Biology, published online (https://doi.org/10.17912/micropub.biology.000248), 2020.
Richards KA, Rubenstein EM (2020). Endoplasmic reticulum stress-regulated degradation of a translocon-associated protein is independent of integrated stress response transcription factor Gcn4p. microPublication Biology, published online (https://doi.org/10.17912/micropub.biology.000239), 2020.
Runnebohm AM, Evans MD, Richardson AE, Turk SM, Olesen JB, Smaldino PJ, Rubenstein EM. Loss of protein quality control gene UBR1 sensitizes Saccharomyces cerevisiae to the aminoglycoside hygromycin B. Fine Focus. In press.
Buchanan BW, Mehrtash AB, Broshar CL, Runnebohm AM, Snow BJ, Scanameo LN, Hochstrasser M, Rubenstein EM. Endoplasmic reticulum stress differentially inhibits endoplasmic reticulum and inner nuclear membrane protein quality control degradation pathways. Journal of Biological Chemistry 294 (19814–19830), 2019.
Niekamp JM, Evans MD, Scott AR, Smaldino PJ, Rubenstein EM. TOM1 confers resistance to the aminoglycoside hygromycin B in Saccharomyces cerevisiae. microPublication Biology, published online (https:// 10.17912/micropub.biology.000193), 2019.
Walls JT, Wyatt KH, Doll JC, Rubenstein EM, Rober AR. Hot and toxic: Temperature regulates microcystin release from cyanobacteria. Science of the Total Environment 610–611 (786–795), 2018.
Engle SM, Crowder JJ, Watts SG, Indovina CJ, Coffey SZ, Rubenstein EM. Acetylation of N-terminus and two internal amino acids is dispensable for degradation of a protein that aberrantly engages the endoplasmic reticulum translocon. PeerJ 5:e3728, 2017.
Buchanan BW, Lloyd ME, Engle SM, Rubenstein EM. Cycloheximide chase analysis of protein degradation in Saccharomyces cerevisiae. The Journal of Visualized Experiments 110 (e53975), 2016.
Ray DB, Merrill GA, Brenner FJ, Lytle LL, Lam T, McElhinney A, Anders J, Rock TT, Lyker JK, Barcus S, Leslie KH, Kramer JM, Rubenstein EM, Schanz KP, Parkhurst AJ, Peck M, Good K, Granath KL, Cifra N, Detweiler JW, Stevens L, Albertson R, Deir R, Stewart E, Wingard K, Richardson MR, Blizard SB, Gillespie LE, Rzewnicki DI, Jones DH. T24 HRAS Transformed NIH/3T3 Mouse Cells (GhrasT-NIH/3T3) in Serial Tumorigenic Passages Give Rise to Increasingly Aggressive Tumorigenic Cell Lines T1-A and T2-A and Metastatic Cell Lines T3-HA and T4-PA. Experimental Cell Research 340 (1 – 11), 2016.
Crowder JJ, Geigges M, Gibson RT, Fults ES, Buchanan BW, Sachs N, Schink A, Kreft SG, Rubenstein EM. Rkr1/Ltn1 Ubiquitin Ligase-Mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins. The Journal of Biological Chemistry 290 (18454-18466), 2015.
Watts SG, Crowder JJ, Coffey SC, Rubenstein EM. Growth-based determination and biochemical confirmation of genetic requirements for protein degradation in Saccharomyces cerevisiae. The Journal of Visualized Experiments 96 (e52428), 2015.
Zattas D, Adle DJ, Rubenstein EM, Hochstrasser M. N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates. Molecular Biology of the Cell 24 (890-900), 2013.
Rubenstein EM. Quality control at the endoplasmic reticulum translocon. Salud (i) Ciencia, 2013. Published online.
Rubenstein EM, Kreft SG, Greenblatt W, Swanson RJ, Hochstrasser M. Aberrant substrate engagement of the Sec61 translocon triggers degradation by the Hrd1 ubiquitin ligase. The Journal of Cell Biology 197, No. 6 (761-773), 2012.
Rubenstein EM, Hochstrasser M. Redundancy and variation in the ubiquitin-mediated proteolytic targeting of a transcription factor. Cell Cycle 9, No. 21 (4282-4285), 2010.
Rubenstein EM, Schmidt MC. The glucose signal and metabolic p[H+]lux. EMBO Journal 29, No. 15 (2473-2474), 2010.
Xie Y, Rubenstein EM, Matt T, Hochstrasser M. SUMO-independent in vivo activity of a SUMO-targeted ubiquitin ligase toward a short-lived transcription factor. Genes and Development 24, No. 9 (893-903), 2010.
Rubenstein EM, McCartney RR, Zhang C, Shokat KM, Shirra MK, Arndt KM, Schmidt MC. Access denied: Snf1 activation loop phosphorylation is controlled by availability of the phosphorylated threonine 210 to the PP1 phosphatase. Journal of Biological Chemistry 283, No. 1 (222-230), 2008.
Rubenstein EM, Schmidt MC. Mechanisms regulating the protein kinases of Saccharomyces cerevisiae. Eukaryotic Cell 6, No. 4 (571-583), 2007.
Elbing K, Rubenstein EM, McCartney RR, Schmidt MC. Subunits of the Snf1 kinase heterotrimer show interdependence for association and activity. Journal of Biological Chemistry 281, No. 36 (26170-26180), 2006.
Rubenstein EM, McCartney RR, Schmidt MC. Regulatory Domains of the Snf1-Activating Kinases Determine Pathway Specificity. Eukaryotic Cell 5, No.4 (620-627), 2006.
McCartney RR, Rubenstein EM, Schmidt MC. Snf1 kinase complexes with different beta subunits display stress-dependent preferences for the three Snf1-activating kinases. Current Genetics 47, No. 6 (335-344), 2005.