J. Wade Harper
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View article: Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders
Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders Open
Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and recycling building blocks for organelle biogenesis. Lysosomal Storage Disorders (LSDs) comprise a broad group of diseases affecting l…
View article: The functional landscape of the human ubiquitinome
The functional landscape of the human ubiquitinome Open
Protein ubiquitination regulates cell biology through diverse avenues, from quality control-linked protein degradation to signaling functions such as modulating protein-protein interactions and enzyme activation. Mass spectrometry-based pr…
View article: α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation
α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation Open
α-Synuclein aggregation is a hallmark of Parkinson's disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naive cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein aggregat…
View article: Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation
Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation Open
Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution…
View article: ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution
ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution Open
Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incom…
View article: Multimodal cell maps as a foundation for structural and functional genomics
Multimodal cell maps as a foundation for structural and functional genomics Open
Human cells consist of a complex hierarchy of components, many of which remain unexplored 1,2 . Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence i…
View article: The network response to Egf is tissue-specific
The network response to Egf is tissue-specific Open
Epidermal growth factor receptor (Egfr)-driven signaling regulates fundamental homeostatic processes. Dysregulated signaling via Egfr is implicated in numerous disease pathologies and distinct Egfr-associated disease etiologies are known t…
View article: EndoMAP.v1, a Structural Protein Complex Landscape of Human Endosomes
EndoMAP.v1, a Structural Protein Complex Landscape of Human Endosomes Open
Early/sorting endosomes are dynamic organelles that play key roles in proteome control by triaging plasma membrane proteins for either recycling or degradation in the lysosome 1,2,3 . These events are coordinated by numerous transiently-as…
View article: Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST
Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST Open
Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomi…
View article: α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation
α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation Open
SUMMARY α-Synuclein aggregation is a hallmark of Parkinson’s disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naïve cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein …
View article: Endo-IP and lyso-IP toolkit for endolysosomal profiling of human-induced neurons
Endo-IP and lyso-IP toolkit for endolysosomal profiling of human-induced neurons Open
Plasma membrane protein degradation and recycling are regulated by the endolysosomal system, wherein endocytic vesicles bud from the plasma membrane into the cytoplasm and mature into endosomes and then degradative lysosomes. As such, the …
View article: Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways
Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways Open
A hallmark of neurodegenerative diseases (NDs) is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degr…
View article: Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases
Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases Open
Specificity of the ubiquitin-proteasome system depends on E3 ligase-substrate interactions. Many such pairings depend on E3 ligases binding to peptide-like sequences - termed N- or C-degrons - at the termini of substrates. However, our kno…
View article: Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2
Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2 Open
PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-s…
View article: Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons
Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons Open
Plasma membrane protein degradation and recycling is regulated by the endolysosomal system, wherein endosomes bud from the plasma membrane into the cytosol and mature into degradative lysosomes. As such, the endolysosomal system plays a cr…
View article: Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways
Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways Open
A hallmark of neurodegenerative diseases is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradatio…
View article: Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets
Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets Open
Numerous metabolic enzymes translocate from the ER membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is im…
View article: Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists
Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists Open
Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 3 (NLRP3) is an innate immune sensor that forms an inflammasome in response to various cellular stressors. Gain-of-function mutations in NLRP3 cause autoinfl…
View article: Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST
Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST Open
SUMMARY Lysosomal storage diseases (LSDs) comprise ∼50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based …
View article: Endosomal, lysosomal, mitochondrial, or Golgi immunoprecipitation for quantitative proteomics v1
Endosomal, lysosomal, mitochondrial, or Golgi immunoprecipitation for quantitative proteomics v1 Open
Previous studies have developed methods for the immunoisolation of lysosomes, mitochondria, EEA1-positive endosomes, Golgi, and other organelles from non-denaturing / non-detergent extracts. Here we describe our most up-to-date protocols f…
View article: Combinatorial selective ER-phagy remodels the ER during neurogenesis
Combinatorial selective ER-phagy remodels the ER during neurogenesis Open
The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the proces…