Robert Piper, PhD
Introduction
Ubiquitin Mediated Trafficking to the Lysosomal Degradative Pathway
Our laboratory is interested in how proteins are degraded in lysosomes. This is a fundamental process of all eukaryotic cells necessary for regulating a variety of cell surface proteins. This process is often termed "downregulation", and is a central feature of virtually all physiological processes that rely on cell surface membrane proteins. Failure to properly downregulate particular proteins can lead to or exacerbate a variety of pathophysiological conditions such as cancer, hypertension, and cardiac disease. Our overall goal is to understand the protein machinery common in all cell types that controls the delivery of membrane proteins to the lysosome. There are two processes that we examine: the first is how proteins are designated and recognized for delivery to the lysosome. The second is how transport through the endocytic pathway via endosome membrane fusion events is controlled. Our primary focus is one finding out how individual "cargo" proteins are selected and designated for transport and degradation in the lysosome. Membrane proteins can initiate their journey to lysosomes from a number of cellular compartments. At the cell surface, proteins can enter the endocytic pathway via internalization. At the Golgi apparatus, proteins can be sorted into transport vesicles that are targeted to endosomes. Perhaps the most critical sorting step controlling the degradation of membrane proteins in lysosomes, is the incorporation of protein cargo into vesicles that bud into the lumen of the endosome. This sorting step occurs within endosomes and leads to the formation of multivesiculated bodies (MVBs) that accumulate lumenal membranes. These lumenal membranes are then subject to degradation by lysosomal lipases and proteases, thereby ensuring the complete destruction of integral membrane proteins. A variety of studies in both yeast and mammalian cells have established that all of these sorting steps can be controlled by the post-translational attachment of ubiquitin. Ubiquitin is a 76 amino acid peptide that is covalently linked to lysine residues via an isopeptide bond. When attached to membrane proteins, ubiquitin acts as a sorting signal to incorporate cargo into transport vesicles that ultimately leads to their delivery to lysosomes. Currently we are determining how ubiquitinated cargo is recognized and incorporated into transport vesicles destined for the lysosome.
Current Positions
- Professor of Molecular Physiology and Biophysics
- Professor of Internal Medicine
- Associate Dean for Research
- Director, College of Medicine Core Research Facilities
- Interim Chair and Departmental Executive Officer, Anatomy and Cell Biology
Education
- BA in Biology, Reed College, Portland, OR
- PhD in Cell Biology & Molecular Biology, Washington University, St. Louis
- Fellow in Microbiology, Oregon Health Sciences University, Portland, OR
- Fellow in Molecular Biology, Institute of Molecular Biology, University of Oregon, Eugene, OR
Graduate Program Affiliations
Center, Program and Institute Affiliations
Research Interests
- How ubiquitin is used as a sorting signal for degrading membrane proteins in lysosomes
Selected Publications
- Pashkova N, Peterson TA, Ptak CP, Winistorfer SC, Guerrero-Given D, Kamasawa N, Ahern CA, Shy ME, Piper RC. Disrupting the transmembrane domain interface between PMP22 and MPZ causes peripheral neuropathy. iScience. 2024 Sep 19;27(11):110989. doi: 10.1016/j.isci.2024.110989. PMID: 39759075; PMCID: PMC11700639.
- Schultz DF, Davies BA, Payne JA, Martin CP, Minard AY, Childs BG, Zhang C, Jeganathan KB, Sturmlechner I, White TA, de Bruin A, Harkema L, Chen H, Davies MA, Jachim S, LeBrasseur NK, Piper RC, Li H, Baker DJ, van Deursen J, Billadeau DD, Katzmann DJ. Loss of HD-PTP function results in lipodystrophy, defective cellular signaling and altered lipid homeostasis. J Cell Sci. 2024 Sep 15;137(18):jcs262032. doi: 10.1242/jcs.262032. Epub 2024 Sep 27. PMID: 39155850; PMCID: PMC11449442.
- Shenoy SK, Grimsey NJ, Piper RC. Editorial: Regulation of hormone and growth factor signalling by ubiquitin and ubiquitin-like protein modifications. Front Endocrinol (Lausanne). 2024 Mar 22;15:1397685. doi: 10.3389/fendo.2024.1397685. PMID: 38586453; PMCID: PMC10995326.
- Pashkova N, Peterson TA, Ptak CP, Winistorfer SC, Ahern CA, Shy ME, Piper RC. PMP22 associates with MPZ via their transmembrane domains and disrupting this interaction causes a loss-of-function phenotype similar to hereditary neuropathy associated with liability to pressure palsies (HNPP). bioRxiv [Preprint]. 2023 Dec 24:2023.12.24.573255. doi: 10.1101/2023.12.24.573255. PMID: 38187781; PMCID: PMC10769442.
- Ptak CP, Peterson TA, Hopkins JB, Ahern CA, Shy ME, Piper RC. Homomeric interactions of the MPZ Ig domain and their relation to Charcot-Marie-Tooth disease. Brain. 2023 Dec 1;146(12):5110-5123. doi: 10.1093/brain/awad258. PMID: 37542466; PMCID: PMC10690024.
- Minard AY, Clark CJ, Ahern CA, Piper RC. Beta-subunit-eliminated eHAP expression (BeHAPe) cells reveal subunit regulation of the cardiac voltage-gated sodium channel. J Biol Chem. 2023 Sep;299(9):105132. doi: 10.1016/j.jbc.2023.105132. Epub 2023 Aug 6. PMID: 37544648; PMCID: PMC10506104.
- Sun H, Weidner J, Allamargot C, Piper RC, Misurac J, Nester C. Dynein-Mediated Trafficking: A New Mechanism of Diabetic Podocytopathy. Kidney360. 2023 Feb 1;4(2):162-176. doi: 10.34067/KID.0006852022. Epub 2022 Dec 6. PMID: 36821608; PMCID: PMC10103215.
- Tseng CC, Piper RC, Katzmann DJ. Bro1 family proteins harmonize cargo sorting with vesicle formation. Bioessays. 2022 Aug;44(8):e2100276. doi: 10.1002/bies.202100276. Epub 2022 Jun 30. PMID: 35770783; PMCID: PMC9575758.
- Azarnia Tehran D, Kochlamazashvili G, Pampaloni NP, Sposini S, Shergill JK, Lehmann M, Pashkova N, Schmidt C, Löwe D, Napieczynska H, Heuser A, Plested AJR, Perrais D, Piper RC, Haucke V, Maritzen T. Selective endocytosis of Ca2+-permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity. Sci Adv. 2022 May 27;8(21):eabl5032. doi: 10.1126/sciadv.abl5032. Epub 2022 May 25. PMID: 35613266; PMCID: PMC9132451.
- Pashkova N, Yu L, Schnicker NJ, Tseng CC, Gakhar L, Katzmann DJ, Piper RC. Interactions of ubiquitin and CHMP5 with the V domain of HD-PTP reveals role for regulation of Vps4 ATPase. Mol Biol Cell. 2021 Dec 1;32(22):ar42. doi: 10.1091/mbc.E21-04-0219. Epub 2021 Sep 29. PMID: 34586919; PMCID: PMC8694081.