Malaiyalam Mariappan, PhD
Associate Professor in Cell Biology
Research & Publications
Biography
Locations
Research Summary
Protein Quality Control and Human Diseases: Our laboratory is interested in understanding how cells detect misfolded proteins and prevent protein aggregation in the cell. Since cells are continually exposed to various stress stimuli, proteins have a high probability of mislocalization, misfolding, aggregating, and causing cellular toxicity and human diseases. To tackle these problems, eukaryotic cells have evolved sophisticated molecular machinery for detecting and eliminating of misfolded proteins in the cell. Our goal is to identify and understand the components involved in various cellular quality control processes.
Currently, our lab is focusing on how the endoplasmic reticulum associated degradation (ERAD) pathway accurately recognizes misfolded proteins in the ER and retro-translocate them into the cytosol. How these retrotranslocated proteins are delivered to the proteasome for degradation (Figure 1A). Our second goal is to understand how the UPR sensors (IRE1, ATF6, and PERK) detect misfolded proteins in the ER and transduce the information to the cytosol and nucleus to upregulate chaperones for improving the ER folding capacity (Figure 1B). Our third goal is to figure out why dysfunction or overloading of proteasomes leads to accumulation and aggregation of misfolded proteins in the cytosol. How these protein aggregates affect the cellular physiology to cause many devastating neurodegenerative diseases including Alzheimer's, Retinitis Pigmentosa and prion diseases (Figure 1C). We use a variety of techniques, including molecular genetic analysis in tissue culture cells, biochemical, structural and high-resolution imaging approaches.
Coauthors
Research Interests
Endoplasmic Reticulum; Quality Control; Protein Folding; Neurodegenerative Diseases; Unfolded Protein Response
Research Images
Selected Publications
- Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins.Culver JA, Mariappan M. Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins. The Journal Of Cell Biology 2021, 220.
- Lonely ER Membrane Proteins Travel to the Nucleus to Rest in Peace by the Asi Complex.Sun S, Mariappan M. Lonely ER Membrane Proteins Travel to the Nucleus to Rest in Peace by the Asi Complex. Molecular Cell 2020, 77:1-2.
- C-terminal tail length guides insertion and assembly of membrane proteins.Sun S, Mariappan M. C-terminal tail length guides insertion and assembly of membrane proteins. The Journal Of Biological Chemistry 2020, 295:15498-15510.
- Membrane Protein Biogenesis: PAT Complex Pats Membrane Proteins into Shape.Culver JA, Mariappan M. Membrane Protein Biogenesis: PAT Complex Pats Membrane Proteins into Shape. Current Biology : CB 2020, 30:R1387-R1389.
- A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress.Li X, Sun S, Appathurai S, Sundaram A, Plumb R, Mariappan M. A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress. Cell Reports 2020, 33:108563.
- Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells.Albert AE, Adua SJ, Cai WL, Arnal-Estape A, Cline GW, Liu Z, Zhao M, Cao PD, Mariappan M, Nguyen DX. Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells. Molecular Cancer Research : MCR 2019, 17:2343-2355.
- Dynamic changes in complexes of IRE1α, PERK, and ATF6α during endoplasmic reticulum stress.Sundaram A, Appathurai S, Plumb R, Mariappan M. Dynamic changes in complexes of IRE1α, PERK, and ATF6α during endoplasmic reticulum stress. Molecular Biology Of The Cell 2018, 29:1376-1388.
- The Sec61 translocon limits IRE1α signaling during the unfolded protein response.Sundaram A, Plumb R, Appathurai S, Mariappan M. The Sec61 translocon limits IRE1α signaling during the unfolded protein response. ELife 2017, 6.
- A functional link between the co-translational protein translocation pathway and the UPR.Plumb R, Zhang ZR, Appathurai S, Mariappan M. A functional link between the co-translational protein translocation pathway and the UPR. ELife 2015, 4.
- Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction.Peng J, Alam S, Radhakrishnan K, Mariappan M, Rudolph MG, May C, Dierks T, von Figura K, Schmidt B. Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction. The FEBS Journal 2015, 282:3262-74.
- Proprotein convertases process and thereby inactivate formylglycine-generating enzyme.Ennemann EC, Radhakrishnan K, Mariappan M, Wachs M, Pringle TH, Schmidt B, Dierks T. Proprotein convertases process and thereby inactivate formylglycine-generating enzyme. The Journal Of Biological Chemistry 2013, 288:5828-39.
- Protein targeting and degradation are coupled for elimination of mislocalized proteins.Hessa T, Sharma A, Mariappan M, Eshleman HD, Gutierrez E, Hegde RS. Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature 2011, 475:394-7.
- The mechanism of membrane-associated steps in tail-anchored protein insertion.Mariappan M, Mateja A, Dobosz M, Bove E, Hegde RS, Keenan RJ. The mechanism of membrane-associated steps in tail-anchored protein insertion. Nature 2011, 477:61-6.
- A conserved archaeal pathway for tail-anchored membrane protein insertion.Sherrill J, Mariappan M, Dominik P, Hegde RS, Keenan RJ. A conserved archaeal pathway for tail-anchored membrane protein insertion. Traffic (Copenhagen, Denmark) 2011, 12:1119-23.
- A ribosome-associating factor chaperones tail-anchored membrane proteins.Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature 2010, 466:1120-4.
- In vitro dissection of protein translocation into the mammalian endoplasmic reticulum.Sharma A, Mariappan M, Appathurai S, Hegde RS. In vitro dissection of protein translocation into the mammalian endoplasmic reticulum. Methods In Molecular Biology (Clifton, N.J.) 2010, 619:339-63.
- The structural basis of tail-anchored membrane protein recognition by Get3.Mateja A, Szlachcic A, Downing ME, Dobosz M, Mariappan M, Hegde RS, Keenan RJ. The structural basis of tail-anchored membrane protein recognition by Get3. Nature 2009, 461:361-6.
- The non-catalytic N-terminal extension of formylglycine-generating enzyme is required for its biological activity and retention in the endoplasmic reticulum.Mariappan M, Gande SL, Radhakrishnan K, Schmidt B, Dierks T, von Figura K. The non-catalytic N-terminal extension of formylglycine-generating enzyme is required for its biological activity and retention in the endoplasmic reticulum. The Journal Of Biological Chemistry 2008, 283:11556-64.
- ERp44 mediates a thiol-independent retention of formylglycine-generating enzyme in the endoplasmic reticulum.Mariappan M, Radhakrishnan K, Dierks T, Schmidt B, von Figura K. ERp44 mediates a thiol-independent retention of formylglycine-generating enzyme in the endoplasmic reticulum. The Journal Of Biological Chemistry 2008, 283:6375-83.
- Paralog of the formylglycine-generating enzyme--retention in the endoplasmic reticulum by canonical and noncanonical signals.Gande SL, Mariappan M, Schmidt B, Pringle TH, von Figura K, Dierks T. Paralog of the formylglycine-generating enzyme--retention in the endoplasmic reticulum by canonical and noncanonical signals. The FEBS Journal 2008, 275:1118-30.
- Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K, Ficner R, Rudolph MG. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell 2005, 121:541-552.
- Molecular characterization of the human Calpha-formylglycine-generating enzyme.Preusser-Kunze A, Mariappan M, Schmidt B, Gande SL, Mutenda K, Wenzel D, von Figura K, Dierks T. Molecular characterization of the human Calpha-formylglycine-generating enzyme. The Journal Of Biological Chemistry 2005, 280:14900-10.
- Crystal structure of human pFGE, the paralog of the Calpha-formylglycine-generating enzyme.Dickmanns A, Schmidt B, Rudolph MG, Mariappan M, Dierks T, von Figura K, Ficner R. Crystal structure of human pFGE, the paralog of the Calpha-formylglycine-generating enzyme. The Journal Of Biological Chemistry 2005, 280:15180-7.
- Expression, localization, structural, and functional characterization of pFGE, the paralog of the Calpha-formylglycine-generating enzyme.Mariappan M, Preusser-Kunze A, Balleininger M, Eiselt N, Schmidt B, Gande SL, Wenzel D, Dierks T, von Figura K. Expression, localization, structural, and functional characterization of pFGE, the paralog of the Calpha-formylglycine-generating enzyme. The Journal Of Biological Chemistry 2005, 280:15173-9.
- Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme.Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, von Figura K. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme. Cell 2003, 113:435-44.