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Sanjay K. Mishra, PhD
- Research Assistant Professor
Misfolding of CFTR (Phe508del) is the major disease-causing misfolded proteins. There are more than 2000 CFTR gene variants has been identified, however all the variants doesnot contribute to the CF disease conditions. Cellular folding of wild type and mutant CFTR is somewhat different and also depends on the cell types. In our lab role of small heat shock proteins in ubiquitination and sumoylation of mutant CFTR is ongoing project. In a Protein Array analysis a number of new protein partners has been identified, which could help in CFTR function. We are trying to establish the percentage of misfolded CFTR proteins degraded by different modifiers such as ubiquitination and Sumoylation and potential possible of role played by small heat shock proteins. Aggregated proteins are selectively degraded by a phenomenon known as aggrepathy (macroautophagy). Recently discovered one such mechanism is mediated-by multifunctional HSP70 co-chaperone BAG3 (BCL2 associated athenogene 3) under severe cellular stress or ageing of the cells. Recently, we have shown that BAG3 in partner with HSP70 and Hsp22 as well as ubiquitin receptor p62 specifically targets aggregation prone ∆F508 CFTR proteins towards autophagic degradation. Here we have evidence now, that co-chaperone BAG3 and autophagy receptor p62 associates with number of associated proteins not found in the CFTR degradation pathway under the perturbation of proteasome. Plethora of interactions among selective misfolded protein and different ubiquitinating recognizing partners play a systematic targeting of different CFTR misfolded proteins to different targets for its degradation to maintain cell homeostasis.
Professional and Scientific Society Memberships:
- German Academic Exchange Services, 1996
- American Society of Cell Biology, 2001-Present
Education & Training
- PhD, Plant Physiology, Biochemistry, Jawaharlal Nehru University, India, 1994
Selected Publications
Zahid M, McCandless K, Mishra S.K., Stiltner J, Feldman K, Yagi H, Yurko R, Islam K, Brown J, Frizzell R.(2021) Novel Lung Targeting Cell-Penetrating Peptides as Vectors for Delivery of Therapeutics. Res Sq. rs.3.rs-1056707. doi: 10.21203/rs.3.rs-1056707/v1. Preprint.
Hutt, D*., Mishra, S.K*, Roth D.M., Larsen, M.B., Angles, F., Frizzell, R.A. and Balch W.E. (2018) Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. J. Biol. Chem. 293 (35), 13682-13695.
Bertrand, C.A., Mitra, S., Mishra, S.K., Wang, X., Zhao, Y., Pilewski, J.M., Madden and D.R., Frizzell R.A. (2017) The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9. Am J Physiol Lung Cell Mol Physiol. 2017 Jun1;312(6):L912-L925.
Mishra, S.K., L. Funair, A. Cressley, G.K. Gittes, and R.C. Burns. (2012) High-affinity dkk1 receptor Kremen1 is internalized by clathrin-mediated endocytosis. PLoS ONE. 7 (12):e52190. Epub 2012 Dec 14.
Chen H, G. Houshmand, S. Mishra, G.H. Fong, G.K. Gittes and F. Esni (2010) Impaired pancreatic development in Hif2-alpha deficient mice. Biochem Biophys Res Commun. 399(3): 440-5. Epub 2010 Aug 3.
Reider A., S.L. Barker, S.K. Mishra, Y.J. Im, L. Maldonado-Baez, J.H. Hurley, L.M. Traub and B. Wendland (2009) Syp1 is a conserved endocytic adaptor that contains a domain involved in cargo selection and membrane tubulation. The EMBO J. 28(20), 3103-3116.
Thieman J.R., S.K. Mishra, K. Ling, B. Doray, R.A. Anderson, L.M. Traub (2009) Clathrin Regulates the Association of PIPKI661 with the AP-2 adaptor 2 Appendage. J Biol Chem. 15,284(20), 13924-13939.
Mishra S.K., A. Jha , A.L. Steinhauser, V.A. Kokoza, C.H. Washabaugh, A.S. Raikhel, W.A. Foster and L.M. Traub (2008) Conserved recognition of FxNPxY Internalization signals by Phosphotyrosine-binding domain CLASPs in disease vector Mosquitoes. J. Cell Science. 121(8):1264-1274.
Keyel P.K., Mishra S.K, R. Roth, J.E. Heuser, S.C. Watkins and L.M. Traub (2006) A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors. Mol. Biol. Cell. 17(10), 4300-4317.
Edeling M.A., S.K. Mishra, P.A. Keyel, A.L. Steinhauser, B.M. Collins, R. Roth , J.E. Heuser, D.J. Owen and L.M. Traub (2006) Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly. Dev Cell. 10(3):329-342.
Hawryluk M.J., P.A. Keyel, S.K. Mishra, S.C. Watkins, J.E. Heuser, and L.M. Traub (2006) Epsin 1 is a polyubiquitin-selective clathrin-associated sorting protein. Traffic. 7(3):262-81.
Academic and Research Interests
- CFTR
- Protein Misfolding
- CRISPR-CAS
- Auophagy
- Origami