Ph.D, Nencki Institute
M.Sc, University of Warsaw
Distinguished University Professor
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
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 are investigating the contribution of calreticulin and other ER resident proteins to cardiac pathology including cardiac hypertrophy and heart failure.
ER calcium homeostasis
is an important second messenger. Ca2+
is released from the ER into the cytoplasm and the loss of ER Ca2+
stores necessitates refilling via a process known as store-operated Ca2+
entry (SOCE). We are interested in understanding the role of ER luminal environment in regulation of ER-dependent Ca2+
signaling and its role in human pathology.
ER chaperones and energy metabolism
Disrupted ER homeostasis due to loss of ER chaperones may lead to dysregulation of energy metabolism. We are interested in the mechanisms responsible for ER-dependent modulation of energy metabolism with a special emphasis on the role of ER associated molecular chaperones.
Deciphering a role of ER chaperones in neuropathies
We discovered that calnexin-deficient mice develop a specific neuropathy, dysmyelination and impaired motor function. 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 such as Multiple Sclerosis, amyotrophic lateral sclerosis (ALS) and myelin diseases.
Exogenous calreticulin, incorporated onto non-Infective Trypanosoma cruzi epimastigotes, promotes their internalization into mammal hosts cells.
Sosoniuk-Roche E, Vallejos G, Aguilar L, Pizarro-Bäuerle J, Weinberger K, Rosas C, Valck C, Michalak M and Ferreira A.
Immunobiology (2017) 222:529-535.
The rise of proteostasis promoters.
Vega H, Agellon LB and Michalak M
IUBMB Life (2016) 68: 943-954.
Inhibition of the unfolded protein response mechanism prevents cardiac fibrosis.
Groenendyk J, Lee D, Jung J, Dyck JRB, Lopaschuk GL, Agellon LB, Michalak M.
PLoS ONE (2016) 11: e0159682.
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.
UBC9-dependent associationbetween calnexin and protein tyrosine phosphatase 1B (PTP1B) at the endoplasmic reticulum.
Lee D, Kraus A, Prins D, Groenendyk J, Aubry I, Liu W-X, Li H-D, Julien O, Touret N, Sykes B, Tremblay ML, Michalak M.
J. Biol. Chem. (2015) 290: 5725-5738.
Endoplasmic reticulum stress in preimplantation embryos.
Michalak M, Gye MC.
Clinc. Expt. Reproductive Med. (2015) 42: 1-7.
Calcium and endoplasmic reticulum (ER) stress: an integrated view of calcium signaling.
Krebs J, Agellon LB, Michalak M.
Biochem. Biophys. Res. Commun. (2015) 460: 114-121.
STIM1 is cleaved by calpain.
Prins D, Michalak M.
FEBS Lett. (2015) 589: 3294-3301.
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.
Calreticulin induces dilated cardiomyopathy.
Lee D, Oka T, Hunter B, Robinson A, Papp S, Nakamura K, Srisakuldee W, Nicke BE, Light PE, Dyck JRB, Lopaschuk GL, Kardami E, Opas M, Michalak M.
PLoS ONE (2013) 8:e56387.
Coping with endoplasmic reticulum stress in the cardiovascular system.
Groenendyk J, Agellon LB, Michalak M.
Annu. Rev. Physiol. (2013) 75: 49-67.