Hermann Steller | The Rockefeller University (original) (raw)

Uploads

Papers by Hermann Steller

International Journal of Molecular Sciences, 2016

Nature cell biology, 2000

Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ART... more Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-beta signalling pathway). ARTS is expressed in many cells and acts to enhance cell death induced by TGF-beta or, to a lesser extent, by other apoptotic agents. Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs. Mutation of the P-loop of ARTS abrogates its competence to activate caspase 3 and to induce apoptosis. Taken together, these observations expand the functional attributes of septins previously described as having roles in cytokinesis and cellular morphogenesis.

The Journal of Cell Biology, 2010

Self- and hetero-association of the pro-apoptotic proteins Reaper, Hid, and Grim is required for ... more Self- and hetero-association of the pro-apoptotic proteins Reaper, Hid, and Grim is required for efficient induction of the cell death program.

Cell Death and Differentiation, 2009

Proteasome-mediated degradation of intracellular proteins is essential for cell function and surv... more Proteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse CNS suggests a key role for PI31 in human developmental neurological disorders.

bioRxiv, 2020

Age-related neurodegenerative diseases pose a major unmet health need since no effective treatmen... more Age-related neurodegenerative diseases pose a major unmet health need since no effective treatment strategies are currently available. These disorders are defined by the accumulation of abnormal protein aggregates that impair synaptic function and cause progressive neuronal degeneration. Therefore, stimulating protein clearance mechanisms may be neuro-protective. The proteasome regulator PI31 promotes local protein degradation at synapses by mediating fast proteasome transport in neurites, and loss of PI31 function causes neuronal degeneration. Here we show that transgenic expression of PI31 in a mouse Parkinson’s Disease model preserves neuronal function and greatly extends animal health and lifespan. These results indicate that targeting the PI31-pathway may have therapeutic value for treating neurodegenerative disorders.

Protein degradation by the ubiquitin-proteasome system (UPS) is critical for neuronal development... more Protein degradation by the ubiquitin-proteasome system (UPS) is critical for neuronal development, plasticity and function. Neurons utilize microtubule-dependent molecular motors to allocate proteasomes to synapses, but how proteasomes are coupled to motor proteins and how this transport is regulated to meet changing demand for protein breakdown remains largely unknown. We show that the conserved proteasome-binding protein PI31 serves as an adaptor to directly couple proteasomes with dynein light chain proteins (DYNLL1/2). Inactivation of PI31 inhibits proteasome motility in axons and disrupts synaptic protein homeostasis, structure and function. Moreover, phosphorylation of PI31 at a conserved site by p38 MAP kinase promotes binding to DYNLL1/2, and a non-phosphorable PI31 mutant impairs proteasome movement in axons, suggesting a mechanism to regulate loading of proteasomes onto motor proteins. Because mutations affecting PI31 activity are associated with human neurodegenerative di...

The self-renewal of intestinal stem cell is controlled by Wingless/Wnt-β catenin signaling both i... more The self-renewal of intestinal stem cell is controlled by Wingless/Wnt-β catenin signaling both in Drosophila and mammals. Since Axin is a rate-limiting factor in Wingless signaling its regulation is essential. Iduna is an evolutionarily conserved ubiquitin E3 ligase that has been identified as a critical regulator for degradation of ADP-ribosylated Axin and thus of Wnt/β-catenin signaling. However, its physiological significance remains to be demonstrated. Here, we generated loss-of-function mutants of Iduna to investigate its physiological role in Drosophila. Genetic depletion of Iduna causes the accumulation of both Tankyrase and Axin. Increase of Axin protein in enterocytes non-autonomously enhanced stem cell divisions in the Drosophila midgut. Enterocytes secreted Unpaired and thereby stimulated the activity of the JAK-STAT pathway in intestinal stem cells. A decrease in Axin gene expression suppressed both the over-proliferation of stem cells and restored their numbers to norm...

This article cites 35 articles, 21 of which can be accessed free

Cell reports, Jan 17, 2017

Non-coding RNA biogenesis in higher eukaryotes has not been fully characterized. Here, we studied... more Non-coding RNA biogenesis in higher eukaryotes has not been fully characterized. Here, we studied the Drosophila melanogaster Rexo5 (CG8368) protein, a metazoan-specific member of the DEDDh 3'-5' single-stranded RNA exonucleases, by genetic, biochemical, and RNA-sequencing approaches. Rexo5 is required for small nucleolar RNA (snoRNA) and rRNA biogenesis and is essential in D. melanogaster. Loss-of-function mutants accumulate improperly 3' end-trimmed 28S rRNA, 5S rRNA, and snoRNA precursors in vivo. Rexo5 is ubiquitously expressed at low levels in somatic metazoan cells but extremely elevated in male and female germ cells. Loss of Rexo5 leads to increased nucleolar size, genomic instability, defective ribosome subunit export, and larval death. Loss of germline expression compromises gonadal growth and meiotic entry during germline development.

Human molecular genetics, Jul 9, 2016

Gaucher disease (GD) results from mutations in the acid β-glucocerebrosidase (GCase) encoding gen... more Gaucher disease (GD) results from mutations in the acid β-glucocerebrosidase (GCase) encoding gene, GBA, which leads to accumulation of glucosylceramides. GD patients and carriers of GD mutations have a significantly higher propensity to develop Parkinson disease (PD) in comparison to the non-GD population.In the present study we used the fruit fly Drosophila melanogaster to show that development of PD in carriers of GD mutations results from the presence of mutant GBA alleles. Drosophila has two GBA orthologs (CG31148 and CG31414), each of which has a minos insertion, which creates C-terminal deletion in the encoded GCase. Flies double heterozygous for the endogenous mutant GBA orthologs presented Unfolded Protein Response (UPR) and developed parkinsonian signs, manifested by death of dopaminergic cells, defective locomotion and a shorter life span. We also established transgenic flies carrying the mutant human N370S, L444P and the 84GG variants. UPR activation and development of p...

Apoptosis Fundamentals Pathways Clinical Applications and Role in Disease, Oct 1, 2007

PLoS biology, 2007

PLoS Biology is an open-access, peer-reviewed journal that features works of exceptional signific... more PLoS Biology is an open-access, peer-reviewed journal that features works of exceptional significance in all areas of biological science, from molecules to ecosystems, including works at the interface with other disciplines.