Evidence map›Paper›PMID 41809038›Full record

ArticleiScience2026

Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.

Nayyerehalsadat Hosseini, Ahmed M Elshazly, Holly A Byers, Madison A Ward, Amy N Brooks, Janakiram R Vangala, Senthil K Radhakrishnan

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors.

Nayyerehalsadat HosseiniDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Ahmed M ElshazlyDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Holly A ByersDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Madison A WardDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Amy N BrooksDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Janakiram R VangalaDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Senthil K RadhakrishnanDepartment of Pathology, Virginia Commonwealth University, Richmond, VA, USA.

Funding

Nrf1-dependent Proteotoxic Stress Response - Diversity SupplementR01GM132396 · NIGMS · VIRGINIA COMMONWEALTH UNIVERSITY · PI RADHAKRISHNAN, SENTHIL KUMAR · 2019 to 2023
$1.9M
Integrative Training Program in Cancer BiologyT32CA272382 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI Paula Daniela Bos · 2023 to 2026
$1.3M
NCI NIH HHS T32 CA272382NIGMS NIH HHS R01 GM132396
6 · The paper itself

Abstract

The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are the primary mechanisms for protein degradation, yet the molecular mechanisms linking them remain unclear. We show that loss of the UPS shuttle-protease DDI2 in diverse human and murine cells leads to a proteotoxic stress response driven by the intracellular accumulation of the secretory protein CCN1. Misfolded CCN1 is normally extracted from the endoplasmic reticulum by a DDI2-p97 complex and directed to lysosomes for degradation. In the absence of DDI2, CCN1 builds up, produces reactive oxygen species, and triggers compensatory autophagy; CCN1 knockout or ROS scavenging attenuates this response. Loss of DDI2 also impairs CCN1-LAMP1 colocalization, suggesting that DDI2 functions as a selective cargo receptor linking the UPS and ALP. These findings reveal a stress-responsive DDI2-CCN1 axis that reshapes proteostasis and highlight DDI2 as a potential therapeutic vulnerability in proteasome-dependent cancers.

Indexed as

BiochemistryBiological sciencesCancerCancer systems biologyProteomics

Identifiers

PMID41809038
PMCPMC12969088

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.