Marek Michalak

Research:

Our lab studies the structure and function of endoplasmic reticulum (ER) membranes and the role of this membrane system in the control of intracellular signalling, communication with other intracellular organelles, regulation. Our lab studies the structure and function of endoplasmic reticulum (ER) membranes and the role of this membrane system in the control of intracellular signalling, communication with other intracellular organelles, regulation of protein synthesis and folding, modulation of gene expression and calcium homeostasis. We discovered that ER resident chaperones play critical roles in cardiac development and pathophysiology of the mature heart. The proteins are also key in specific neuropathies. Our long-term goal is to understand ER stress and ER signaling events responsible for the activation and maintenance of intracellular pathways affecting cardiac or neuronal physiology and pathology, and to use this information to devise pharmacological and genetic therapies for the treatment of human disease.

Here are a few examples of research projects currently being pursued in our lab:

Modulators of ER Stress

Using small interfering RNA (siRNA) library screens, we have identified several cellular proteins that regulate ER stress responses and the unfolded protein response (UPR), including ER luminal resident chaperones and folding enzymes. We are pursuing a variety of strategies to use this information to manipulate ER stress pathways and to uncover additional regulators of ER stress.

Calreticulin, ER Resident Proteins and Cardiac Physiology

We apply gene knockout and transgenic techniques to understand the role of ER proteins and the ER luminal environment in embryogenesis and congenital pathologies. We discovered that calreticulin is critical for cardiac development. Modulation of calreticulin expression in the heart results in development of severe cardiomyopathies and complete heart block. We are investigating the contribution of calreticulin and other ER resident proteins to cardiac pathology including cardiac hypertrophy and heart failure.

ER Calcium Homeostasis

Calcium is released from the ER into the cytoplasm and the loss of ER calcium stores necessitates refilling via a process known as store-operated calcium entry (SOCE). Stromal interaction molecule 1 (STIM1) is an ER membrane calcium sensor responsible for activation of store-operated calcium influx. We discovered that STIM1 oligomerization and SOCE are modulated by the ER resident oxidoreductase PDIA3. We also discovered that ER calcium status is important determinant of the basal sensitivity of the sterol sensing mechanism inherent to the SREBP processing pathway. We are interested in understanding the role of ER luminal environment in calcium signaling and in the regulation cholesterol metabolism.

Deciphering a Role of ER Chaperones in Neuropathies

We discovered that calnexin-deficient mice develop a specific neuropathy, dysmyelination and impaired motor function. We identify calnexin in brain endothelial cells as a novel target for developing strategies aimed at managing or preventing the pathogenic cascade that drives neuroinflammation and destruction of the myelin sheath in multiple sclerosis. We are interested in understanding the role of calnexin and ER stress in the pathology of the nervous system with a special emphasis on human neuropathies and myelin diseases.

Selected Publications:

Interplay between calcium and endoplasmic reticulum stress
Groenendyk, J., and Michalak, M. 
Cell Calcium (2023) 113: 102753

Loss of the fructose transporter SLC2A5 inhibits cancer cell migration.
Groenendyk, J., Stoletov, K., Paskevicius, T., Li, W., Dai, N., Pujol, M., Busaan, E., Ng, H.H., Boukouris, A.E., Saleme, B., Haromy, A., Cui, K., Hu, M., Yan, Y., Zhang, R., Michelakis, E., Chen, X-Z., Lewis, J.D., Tang, J., Agellon, L.B. and Michalak, M.   
Frontiers Cell Dev. Biol. (2022) 30: 896297

Inositol Requiring Enzyme (IRE), a multiplayer in sensing endoplasmic reticulum stress
Zhou, Z., Wang, Q. and Michalak, M.   
Animal Cells and Systems. (2021) 25: 347–357

Calcium signaling and endoplasmic reticulum stress
Groenendyk, J., Agellon L.B. and Michalak, M.  
International Review of Cell and Molecular Biology (2021) 363: 1-20

Selective enhancement of cardiomyocyte metabolic efficiency results in a pernicious heart condition.
Groenendyk, J., Wang, Q., Wagg, C., Lee, D., Robinson, A., Banga, S., Barr, A., Light, P., Lopaschuk, G.L., Agellon L.B. and Michalak, M. 2020.  
PLoS ONE. (2020) 15(8): e0236457

ER-associated protein degradation at atomic resolution.
Eldeeb, M.A., Fahlman, R. and Michalak, M. 2020.
Trends in Biochem. Sci. (2020) 45: 723-725

Calsequestrin. Structure, function and evolution.
Wang, Q. and Michalak, M. 2020.
Cell Calcium (2020) 90: 102242

Phylogenetic and biochemical analysis of calsequestrin structure and association of its variants with cardiac disorders.
Wang, Q., Paskevicius, T., Qin, W., Filbert, A., Tang, J., Chen, X.-Z., Dacks, J.B., Agellon, L.B. and Michalak, M.
Scientific Rep (2020) 10: 18115

Two pools of IRE1α in cardiac and skeletal muscle cells.
Wang Q, Groenendyk J, Paskevicius T, Qin W, Kor KC, Liu Y, Hiess F, Knollmann BC, Chen SRW, Tang J, Chen XZ, Agellon LB, Michalak M.
FASEB J. 2019 Aug;33(8):8892-8904.

Endoplasmic reticulum calcium dictates the distribution of intracellular unesterified cholesterol.
Wang WA, Agellon LB, Michalak M.
Cell Calcium. (2018) Dec;76:116-121.

Stress Coping Strategies in the Heart: An Integrated View.
Michalak M, Agellon LB.
Front Cardiovasc Med. (2018) Nov 21;5:168.

Calnexin is necessary for T-cell transmigration into the central nervous system.
Jung J, Eggleton P, Robinson A, Wang J, Gutowski N, Holley J, Dudek E, Paul A, Zochodne D, Kraus A, Power C, Agellon LB and Michalak M
J. Clinic. Invest. insight (2018) 3: e98410

Cyclosporine A binding to COX-2 reveals a novel signaling pathway that activates IRE1α unfolded protein response sensor
Groenendyk J, Paskevicius T, Urra H, Viricel C, Wang K, Barakat K, Hetz C, Kurgan L, Agellon LB and Michalak M
Scientific Rep. (2018) 8: 16678

Interactome screening identifies the ER luminal chaperone Hsp47 as a novel regulator of the unfolded protein response (UPR) transducer IRE1α.
Sepulveda D, Rojas-Rivera D, Groenendyk J, Rodríguez DA, Köhler A, Lebeaupin C, Ito S, Urra H, Carreras-Sureda A, Chevet E, Campos G, Godoy P, Vaisar T, Glimcher L, Bailly-Maitre B, Nagata K, Michalak M, Sierralta J and Hetz C
Molecular Cell (2017) 69: 238-252

Calreticulin secures calcium-dependent nuclear pore competency required for cardiogenesis.
Faustino RS, Behfar A, Groenendyk J, Wyles SP, Niederlander N, Puceat M, Michalak M, Terzic A, Perez-Terzic C
J. Mol. Cell. Cardiol. (2016) 92: 63-74.

Endoplasmic reticulum stress in preimplantation embryos.
Michalak M, Gye MC.
Clinc. Expt. Reproductive Med. (2015) 42: 1-7.

Interplay between PDIA6 and miR-322 controls adaptive response to disrupted endoplasmic reticulum calcium homeostasis.
Groenendyk J, Peng Z, Dudek E, Fan X, Mizianty MJ, Dufey E, Urra H, Sepulveda D, Rojas-Rivera D, Yunki L, Kim DH, Baretta K, Srikanth S, Gwack G, Ahnn J, Kaufman RJ, Lee S-K, Hetz C, Kurgan L, Michalak M.
Science Signaling. (2014) 7 (329): ra54.

Coping with endoplasmic reticulum stress in the cardiovascular system.
Groenendyk J, Agellon LB, Michalak M.
Annu. Rev. Physiol. (2013) 75: 49-67.