Michael Ehrmann

Cellular proteostasis relies on the coordinated action of molecular chaperones and protein degradation pathways to maintain protein folding and turnover. While the roles of chaperones and the proteasome are well established, how ubiquitin E3 ligases contribute to the proteostasis network remains incompletely understood. Here, we analyzed proteostasis in melanoma cells using quantitative proteomics under mild protein folding stress induced by HSP90 and proteasome inhibition. We identified the HECT-type E3 ligase TRIP12 as a proteostasis-responsive factor that was upregulated upon proteasome inhibition. Depletion of TRIP12 led to protein accumulation of a distinct group of epigenetic and transcriptional regulators, suggesting that these proteins may constitute a novel class of TRIP12 targets. Notably, the loss of TRIP12 led to a widespread reduction in the abundance of many other proteins, including components of the proteostasis network, particularly ubiquitin E3 ligases. These changes occurred largely without corresponding mRNA alterations, indicating post-transcriptional regulation. HSP90 inhibition similarly reduced protein abundance and acted in an additive manner with TRIP12 depletion to further destabilize the proteome. Together, our findings suggest that TRIP12 functions as a regulator of the E3 ligase network and proteostasis capacity, and that its loss, particularly under folding stress, causes a reduction of global protein content. These results reveal an unexpected role for TRIP12 in maintaining proteome stability and support the functional interplay between ubiquitin ligases and molecular chaperones in buffering proteotoxic stress.

Recent advances in mitochondrial network dynamic and signalling highlight mitochondria as key therapeutic targets across diverse diseases. Yet, high drug development failure rates reflect an incomplete understanding of upstream molecular regulators of mitochondrial fate. Here, we address this gap by reverse engineering of the BH3-only protein BNIP3. Structural modelling and sequence–function analyses of its N-terminus identify a critical functional domain and amino acid hotspots that directly activate BCL-2 executioner proteins, triggering mitochondrial cell death. Leveraging these insights, we develop a BNIP3 antagonist peptide (B-017) that disrupts interactions between BNIP3 and BCL-2 executioner proteins, preserving mitochondrial integrity. B-017 demonstrates target specificity, a favourable safety profile, and robust suppression of cell death signalling in human cells. In clinically relevant animal models, it reduces tissue damage in the heart, brain, and liver. Together, these findings position B-017 as a promising therapeutic candidate targeting mitochondrial dysfunction.

Cellular stress response pathways support cell survival under stress and are often leveraged by cancer cells to gain advantageous traits. How cells respond to Golgi stress is incompletely understood, limiting insights into the role of Golgi stress in cancer. Here, we combined small-molecule stress models and proteomic analyses to elucidate stress-induced changes at the Golgi. Our data establish the depletion of Golgi transport proteins as a common response to different Golgi stressors, including ionophores and oxysterol-binding protein (OSBP) inhibitors. Ionophores further induce de novo expression of the stress response protein FAM129A (also known as NIBAN1), which localizes to the remodeled secretory pathway. In a group of melanoma cells, displaying a dedifferentiated epithelial-to-mesenchymal-transition (EMT)-like phenotype, FAM129A is constitutively expressed. In these cells, stress-induced localization of FAM129A to the secretory pathway is achieved by relocalization from the plasma membrane. Collectively, our data highlight the Golgi–endosome interface as a critical hub of the cellular response to Golgi stress and reveal cancer cell-specific effects of this response.

Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis but there is no reliable in vivo model for better understanding this disease. Here, we develop a transgenic mouse model producing a human AL LC. We show that the soluble full length LC is not toxic but a single injection of pre-formed amyloid fibrils or an unstable fragment of the LC leads to systemic amyloid deposits associated with early cardiac dysfunction. AL fibrils in mice are highly similar to that of human, arguing for a conserved mechanism of amyloid fibrils formation. Overall, this transgenic mice closely reproduces human cardiac AL amyloidosis and shows that a partial degradation of the LC is likely to initiate the formation of amyloid fibrils in vivo, which in turn leads to cardiac dysfunction. This is a valuable model for research on AL amyloidosis and preclinical evaluation of new therapies.

SUMMARY: Tauopathies such as Alzheimer’s disease, frontotemporal dementia with Parkinsonism, and other neurodegenerative disorders are characterized by the spread of tau pathology from an initial brain region to neuroanatomically connected areas. At the molecular level, spreading involves aggregation of tau in a donor cell, externalization of transmissible fragments of amyloid fibrils, internalization by an acceptor cell, followed by seeded aggregation of endogenous tau. However, the protein quality control mechanisms that counteract tau aggregation, and in particular its spreading process, are not well understood. In this context, a co-migrating factor performing location-independent interference of fibril formation and transmission would be an appropriate conceptual solution. Here, we show that the cell-to-cell transfer of the widely conserved serine protease HTRA1 impedes tau pathology by targeting multiple steps within the spreading process. Our results suggest a defense mechanism against the intercellular spread of pathogenic protein conformations.

Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1^R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.

A survey on monetary policy communication among former members of the Governing Council of the European Central Bank (ECB) reveals that enhancing credibility and trust is viewed as the most important objective of communication. Respondents judge communication with financial markets and experts as adequate, but see room for improvement in communicating with the public. The central bank objective is seen as the most important topic. Several respondents perceived the ECB's inflation aim of “below, but close to, 2%” that was in place at the time as ambiguous and in need of clarification. Overall, there is broad consensus on various communication issues.