1. What Is Proteostasis?

Proteostasis, blend of “protein homeostasis”, is characterized by the dynamic equilibrium that x sustains the cell’s functional proteome across the entire lifetime of every protein: from synthesis by ribosomes, through folding, post-translational modification, trafficking and assembly into complexes, to their targeting to specific cellular locations and eventual degradation. Far from being a static state, proteostasis is a continuously recalibrated balance between protein production, quality control and clearance, capable of adapting to the constantly changing demands of the cellular environment through the activation of specific signaling pathways.

This balance depends on an integrated proteostasis network (PN) composed of molecular chaperones and co-chaperones, the ubiquitin-proteasome system, the autophagy-lysosomal machinery, stress-response pathways, most notably the unfolded protein response (UPR) at the endoplasmic reticulum and mitochondrion, the integrated stress response (ISR) and the heat shock response (HSR), and compartmentalized quality-control systems^[1]. When this network fails, misfolded or damaged proteins accumulate, aggregate and compromise cellular function, a proteotoxic phenomenon now recognized as a hallmark of aging and as a central mechanism in neurodegenerative, metabolic, cardiovascular and oncological disease^[2,3]. Proteostasis is also controlled and coordinated between cells at the cellular tissue and organismal level^[4], where the nervous system is a central hub for the global coordination and quality control of proteome integrity^[5,6].

2. The Proteostasis Network

Proteostasis does not reside in a single mechanism but in the coordination of multiple interdependent nodes. The principal ones are described below; together they constitute the core thematic scope of this journal.

2.1 Protein synthesis, folding, post-translational modifications and maturation

Translation at the ribosome and co-translational folding constitute the starting point of proteostasis. Ribosomal elongation rates, estimated at roughly 4 to 20 amino acids per second, directly shape the efficiency of nascent-chain folding, while macromolecular crowding in the cytoplasm, with protein concentrations of 200 to 300 mg/mL, can both assist and compromise correct folding.

Molecular chaperones (the Hsp70, Hsp90 and chaperonin families) and their co-chaperones, including the diverse J-domain protein (JDP) family, assist this process by modulating Hsp70 activity, together with proteases forming a powerful intracellular quality-control network^[7]. Protein disulfide isomerases (PDI) are also central players in folding and quality control mechanisms. Multiple post-translational modifications (such as protein glycosylation) and a balanced redox control, in addition to endoplasmic reticulum (ER) luminal calcium concentrations, are also key to sustain protein folding.

2.2 Subcellular compartmentalization, quality control systems and protein trafficking

Each compartment (i.e. endoplasmic reticulum, mitochondrion, nucleus, lysosome) possesses its own quality-control machinery specialized in monitoring the local proteome and ensuring its integrity. Protein trafficking and targeting determine whether a protein reaches its functional destination; at every step along this biosynthetic pathway there is potential for quality-control system failure, underscoring the importance of studying these mechanisms in organs with high secretory and trafficking demands, such as the kidney^[8].

Mitochondrial proteostasis deserves particular attention: it keeps functional a hybrid proteome encoded by both the nuclear and mitochondrial genomes, and its disruption is associated with numerous diseases and with cellular aging itself^[9].

2.3 Degradation systems: The proteasome and autophagy-lysosome pathway

The ubiquitin-proteasome system and the autophagy-lysosomal pathways constitute the principal mechanisms for clearing damaged or unneeded proteins. Autophagy, an evolutionarily conserved process, degrades protein aggregates via the lysosome includes macro-autophagy, micro-autophagy and chaperone-mediated autophagy^[10,11]. Macro-autophagy was recently recognized, in the 2023 update to the hallmarks of aging, as a distinct hallmark separate from the broader loss of proteostasis, given evidence that its inhibition alone is sufficient to induce aging features^[2].

2.4 Signaling responses to proteotoxic stress

When misfolded proteins accumulate, the cell activates emergency transcriptional and translational programs: the UPR in the endoplasmic reticulum and the mitochondria (UPRmt)^[12], the HSR, and the ISR. The UPR was first conceptualized by the discovery that improperly folded proteins in the ER signal the induction of glucose-regulated proteins^[13] and followed by the identification of the ER stress sensor inositol-requiring enzyme 1 (IRE1) independently by Peter Walter’s laboratory^[14] and by Kazutoshi Mori in the Sambrook’s laboratory^[15]. IRE1 was also characterized to signal through unconventional messenger RNA (mRNA) splicing with HAC1 in S. cerevisiae^[16] and X-box binding protein 1 (XBP1) in metazoans^[17-19].

Once activated, the three ER stress sensors, namely inositol-requiring enzyme 1 alpha (IRE1α), protein kinase R-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6), trigger adaptive signaling that expands protein-folding capacity and reduces the protein load on the ER, a duality captured in Walter and Ron’s classic framing of the UPR as moving from a stress pathway to a homeostatic regulatory circuit^[20]. Complementary work from Kaufman and colleagues^[21], and from Hetz and coworkers^[22], has further dissected how the three UPR branches are wired to cell-fate decisions and to the broader proteostasis network. These signaling pathways, together with biomolecular condensation of chaperones and their substrates, integrate the sensing of proteotoxic damage with the reprogramming of a cell’s folding and degradation capacity by controlling protein translation and transcription^[23]. The ISR is mainly controlled by the phosphorylation of the translation initiation factor eIF2a by 4 kinases, namely EIF2AK1 (HRI), EIF2AK2 (PKR), EIF2AK3 (PERK, shared with the UPR), and EIF2AK4 (GCN2)^[24]. The activation of these kinases leads to translation attenuation and in the meantime leads to the activation of specific transcriptional programs mainly through activating transcription factor 4 (ATF4).

The HSR is regulated by master transcription factors, molecular chaperones, and a negative feedback loop. In mammals, the primary controller is heat shock factor 1 (HSF1), regulating many chaperones and other proteostatic mediators^[25]. Activation of HSF1 is regulated by a multistep process initiated by the conversion of monomeric HSF1 to nuclear-localized HSF-1 homotrimers, leading to the upregulation of heat shock genes. Maintenance of HSF-1 in the control state involves weak and transient interactions with chaperones such as Hsp90, Hsp70, and Hsp40^[26]. This chaperone–HSF1 equilibrium is disrupted by the rapid appearance of misfolded proteins in the cytosol, that redirects chaperones to sequester these non-native species, thus releasing HSF1 to self-associate into trimers.

Transcription factor EB (TFEB) is the master regulator of lysosomal biogenesis and autophagy, acting as a key sensor and responder to lysosomal stress. When lysosomes are damaged, starved, or functionally impaired, TFEB moves into the cell nucleus to activate the expression of multiple lysosomal-related genes, boosting cellular clearance and repairing the lysosomes. Central regulators of TFEB include the mechanistic target of rapamycin (mTOR) pathway, a critical homeostatic sensor in the cell. Under normal conditions, active mechanistic target of rapamycin complex 1 (mTORC1) sits on the lysosome surface and traps TFEB in the cytoplasm^[27]. Lysosomal stress or pH changes turn off mTORC1, releasing TFEB to translocate to the nucleus reprogram gene expression.

2.5 Protein aggregation and misfolding disorders

When the mechanisms above are overwhelmed by the burden of damaged proteins, or by aging itself, misfolded species tend to aggregate into insoluble deposits that progressively accumulate within the cell, which could then propagate through prion-like mechanisms^[28]. This proteostasis collapse compromises essential cellular functions in multiple compartments^[29] or degradation systems such as the proteasome and autophagy and constitutes the molecular substrate of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and various motoneuron diseases such as amyotrophic lateral sclerosis, as well as a broad spectrum of systemic proteinopathies^[30-32]. Sustaining proteostasis capacity across the lifespan, including through the UPR and autophagy, is increasingly recognized as central to preventing the abnormal protein aggregation that drives neurodegenerative disease^[4].

2.6 Therapeutic targeting of proteostasis

Small molecules targeting proteostasis modulate protein synthesis, folding, and clearance pathways, they can also directly impact on improperly folded proteins to restore their function in the case of protein misfolding diseases. Key mechanisms include chaperone modulation, ubiquitin-proteasome system (UPS) regulation, and targeted protein degradation. These compounds hold therapeutic potential for neurodegenerative diseases, cancer, and viral infection. Pharmacological modulation of stress responses (i.e. UPR, ISR, HSR) have shown outstanding effects in preclinical models of disease^[24,33], and many compounds have already moved into clinical trials^[24,33,34]. Gene therapy using recombinant viral vectors are also currently under development in preclinical models of disease, showing promising effects in diseases affecting the brain^[4].

3. The Purpose of This Journal

Proteostasis is launched as a quarterly, gold open-access journal published by Science Exploration Press, with a clear purpose: to provide an interdisciplinary platform dedicated to integrating the different nodes of the proteostasis network such as protein folding pathways, subcellular compartments, quality-control mechanisms, stress responses, protein translation, degradation pathways, and protein maturation and targeting, and their roles in physiology and disease.

Because loss of proteostasis is a primary hallmark of aging, one of the journal’s central aims is to build a robust scientific foundation for evidence-based interventions that, by targeting proteostasis, promote health, delay disease and extend longevity. To that end, we seek to drive the integration of cell biology, biochemistry, protein aggregation research, systems biology, targeted interventions (advanced therapies and small molecules), biomarkers, and clinical implementation strategies.

All content is published under the Creative Commons Attribution 4.0 International License (CC BY 4.0): authors retain copyright of their work, which remains freely available for use, copying and redistribution in any format, provided proper citation is given to the original source. Permanent digital archiving through Portico ensures long-term preservation of, and access to, every article the journal publishes.

Positioning: A Global, Interdisciplinary and Disruptive Scope

Proteostasis is conceived, from its first issue, as a genuinely global journal. Protein misfolding, quality control and stress adaptation are universal biological problems, extending even to protein quality-control mechanisms conserved across bacteria^[35], and the research addressing them is produced across every continent—in long-established structural biology and neuroscience centers as much as in emerging research hubs across Latin America, Asia, Africa and Oceania. We actively welcome submissions from laboratories and clinical groups worldwide, regardless of geography, institutional prestige or resource level, and we are committed to an editorial and reviewer board that reflects that same international diversity^[36].

The journal’s scope is deliberately interdisciplinary. Proteostasis sits at the intersection of structural and cell biology, biochemistry, biophysics, genetics, systems biology and computational modeling, neuroscience, immunology, oncology, immunology, nephrology, cardiology as well as plant science or microbiology or geroscience, and increasingly draws on bioengineering, artificial intelligence and drug discovery. We seek to break down the silos that traditionally separate these fields, providing a shared forum where a structural biologist resolving a chaperone-substrate complex, a clinician managing a proteinopathy, and a data scientist modeling proteostasis networks at scale can read, cite and build on one another’s work.

We aim to be deliberately disruptive in what we publish and how we evaluate it: prioritizing mechanistic insight and rigor over novelty for its own sake, welcoming well-designed negative or contradictory results that sharpen the field’s understanding, and encouraging unconventional methodologies, cross-species comparisons and re-analyses of existing datasets that challenge established models of the proteostasis network. A journal dedicated to a single, integrative concept is only useful if it is willing to publish work that complicates as well as confirms the current picture.

Finally, Proteostasis is built to span the full arc from basic science to application, treating the hallmarks-of-aging framework itself as a useful conceptual bridge between mechanism and clinical relevance^[37]. We give equal editorial weight to fundamental discovery with for instance the biophysics of protein folding, the structural logic of chaperone machines, the genetic dissection of quality-control pathways, and to translational and clinical work that moves this knowledge toward biomarkers, small-molecule and biologic therapeutics, gene and cell therapies, and real-world implementation. Our ambition is that a mechanistic finding published in these pages can be traced, over time, through the preclinical and clinical literature that follows it, with the journal itself serving as a continuous thread from bench to bedside.

4. A Call for Submissions

We invite basic researchers, clinicians, computational biologists and developers of advanced therapies from the international scientific community to submit their work to Proteostasis. We welcome original research articles, reviews, short communications, perspectives and other article types covering theoretical, fundamental, preclinical, translational and clinical aspects of proteostasis, including, but not limited to, the following areas:

• Protein synthesis, maturation and trafficking

• Protein degradation (proteasome, autophagy pathways, lysosomes)

• Protein destination and trafficking

• Protein aggregation and protein misfolding disorders

• Protein secretion

• Protein folding, maturation and quality control

• Biomarkers and predictors of health and disease

• New methods and animal models

• Evolution, nomenclature, data reanalysis, big data

• Small molecules and advanced therapies targeting proteostasis

• Clinical trial design and outcomes

• Implementation science

• Systems biology and omics approaches

All manuscripts will undergo a rigorous peer-review process. We particularly encourage the submission of studies that integrate multiple nodes of the proteostasis network, that contribute new methodological tools or animal models, and that translate mechanistic knowledge into biomarkers or therapeutic strategies with clinical potential.

Proteostasis is, ultimately, a condition of possibility for cellular life: without a functional proteome, no physiology is possible. This journal aspires to become the natural meeting point for those who study, from any angle, how cells build, monitor and preserve this balance, and how its loss opens the door to disease and aging. We invite you to be part of this editorial project from its very first issue.

Authors contribution

The authors contributed equally to the conceptualization, original draft writing, and review and editing of the article.

Conflicts of interest

Claudio Hetz serves as the Editor-in-Chief of Proteostasis, and Eric Chevet serves as an Associate Editor of Proteostasis. The authors declare no other conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

None.

Copyright

© The Author(s) 2026.