In the intricate world of cellular biology, the maintenance of protein quality is pivotal to the health and functionality of cells. Fundamental to this maintenance is the enzyme p97, also known as valosin-containing protein (VCP), which plays a critical role in the selective degradation and recycling of aberrant or surplus proteins within cells. Recent groundbreaking research published in Nature Communications has shed light on the indispensable function of p97/VCP in the piecemeal autophagy of aggresomes — specialized structures that sequester misfolded and aggregated proteins, ensuring cellular proteostasis and preventing toxic buildup.
Proteins are the workhorses of the cell, involved in virtually every biological process. However, the protein synthesis machinery occasionally produces misfolded or defective proteins, which, if not promptly and efficiently cleared, can accumulate and precipitate cellular dysfunction. To counter this, cells have evolved a sophisticated quality control system that identifies and removes these harmful protein aggregates. Central to this system is the aggresome pathway, wherein clustered protein inclusions are shuttled to a juxtanuclear location and encaged within a scaffold, effectively quarantining potential cytotoxic species.
The enzyme p97/VCP emerges as a crucial agent in facilitating the clearance of aggresomes. Functioning as a ubiquitin-selective unfoldase, p97/VCP recognizes ubiquitylated protein substrates, harnesses ATPase activity to extract these proteins from complexes, and directs them toward proteasomal degradation or autophagic machinery. Despite the acknowledged importance of aggresomes, the exact mechanisms governing their turnover remained elusive until this comprehensive study highlighted the pivotal role of p97/VCP in the disassembly and degradation processes.
Using advanced cellular and molecular experimental techniques, the research team demonstrated that inhibition of p97/VCP activity leads to the pronounced accumulation of protein aggregates in the cytoplasm. Fluorescent microscopy revealed that under normal conditions, misfolded proteins, marked ubiquitously by ubiquitin moieties and chaperone molecules, are efficiently dismantled and degraded. However, in the absence or blockade of functional p97/VCP, these aggregates persist and coalesce into larger, more toxic inclusions at the periphery of the nucleus, failing to undergo piecemeal autophagy.
This defective clearance mechanism has profound implications for our understanding of neurodegenerative diseases. Intrinsic to disorders such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS) is the presence of pathogenic protein aggregates, known to disrupt neuronal function and propagate cellular stress. Mutations in the p97/VCP gene, previously associated with certain multisystem proteinopathy syndromes, can now be mechanistically linked to compromised aggresome processing, as evidenced by this study’s findings.
The research further postulates a connection between impaired aggresomal disassembly and the formation of Lewy bodies—hallmark inclusions observed in Parkinsonian brains. These spherical proteinaceous deposits intertwine with various molecular species, forming a neurotoxic milieu that exacerbates neuronal death. By elucidating that p97/VCP is required for the piecemeal autophagic degradation of aggresomes, the study provides a molecular basis for understanding how failures in protein quality control pathways could instigate Lewy body formation and subsequent neurodegeneration.
This study also highlights the intricate relationship between ubiquitylation, ATP-dependent protein remodeling, and autophagic pathways. p97/VCP serves as a molecular engine that unfolds and segregates polyubiquitylated proteins from insoluble complexes, channeling them toward lysosomal or proteasomal degradation. This functional versatility is not only critical for aggresome turnover but also underpins broader cellular proteostasis networks that safeguard against proteotoxic stress.
An essential takeaway from the study is the delineation of aggresome dynamics as a multistep, tightly controlled process involving coordinated activity between ubiquitylation enzymes, molecular chaperones, and ATPase-driven unfoldases such as p97/VCP. The inability to mobilize and dismantle aggresomal structures effectively can tilt the balance toward aggregate stability, fostering a cellular environment conducive to disease progression.
In addition to shedding light on fundamental cellular processes, this research opens promising therapeutic avenues for neurodegenerative disorders. Targeting the regulatory machinery of p97/VCP could restore effective protein quality control mechanisms, mitigating aggregate buildup and neuronal loss. Nonetheless, the enzyme’s multifaceted roles necessitate cautious development of therapeutics to avoid unintended disruptions in essential cellular functions.
The multidisciplinary collaboration behind this study, spanning institutions like the Julius-Maximilians-Universität Würzburg and Harvard Medical School, exemplifies the power of integrated approaches combining biochemistry, cell biology, and advanced imaging techniques. Together, these efforts push the frontier in decoding the molecular basis of cellular proteostasis and disease etiology.
As the scientific community continues to unravel the complexities surrounding protein homeostasis, discoveries such as this underscore the delicate interplay between enzymatic function and disease susceptibility. The enzyme p97/VCP, once merely recognized for its role in protein unfolding, now stands at the crossroads of proteostasis and neurodegeneration, reaffirming the necessity of maintaining intracellular protein quality as a linchpin of cellular and organismal health.
Subject of Research: Cells
Article Title: p97/VCP is required for piecemeal autophagy of aggresomes
News Publication Date: 7-May-2025
Web References:
http://dx.doi.org/10.1038/s41467-025-59556-x
Image Credits: Team Buchberger
Keywords: p97/VCP, ubiquitin-selective unfoldase, aggresomes, protein quality control, proteostasis, neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, Lewy bodies, amyotrophic lateral sclerosis, protein aggregation, autophagy
