# Non-canonical Caspase-8 Activation on Autophagosomal Membranes

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2024 · $418,500

## Abstract

Project Summary/Abstract
This project aims to address a significant knowledge gap regarding the mechanism by which VPS37A deficiency
provides a survival advantage for cancer cells, particularly in the context of accumulated intracellular Death-
Inducing Signaling Complexes (iDISC) and impaired autophagic flux. The VPS37A gene, located on 8p22, is
frequently lost in major solid cancers. Our recent findings have highlighted VPS37A as a crucial regulator of
phagophore closure, a pivotal step in the formation of double membrane autophagosomes during autophagy.
Notably, the depletion of VPS37A inhibits phagophore closure, leading to the upregulation of the NF-κB signaling
pathway. This upregulation is dependent on the LC3-conjugation machinery and the autophagy adaptor p62.
Moreover, the inhibition of NF-κB activation through the blockade of IKK or TAK1 induces iDISC-mediated
apoptosis in 8p/VPS37A-deleted cancer cells. Additionally, our analysis of the Cancer Dependency Map portal
revealed that TAK1, along with its cofactor TAB2, demonstrates a strong functional connection with VPS37A in
cancer cell survival. TAK1 and TAB2 are known to localize on autophagosomal membranes. Based on these
compelling observations, we propose that the TAK1/TAB2/NF-κB axis associated with the phagophore serves
as a gatekeeper, suppressing iDISC activation and promoting cancer cell survival. We are in an ideal position to
test this hypothesis in the following Specific Aims: 1) define the phagophore-associated regulators of the
TAK1/NF-κB pathway; 2) define the regulators of iDISC activation upon phagophore closure inhibition; 3) explore
the roles of phagophore-mediated TAK1/NF-kB signaling in tumor development and progression. Successful
implementation of this research will provide valuable insights into the interplay between the TAK1/NF-κB
signaling and iDISC/CASP8 cascade on phagophores to control cell death and survival and pave the way for
future development of new strategies to treat cancers, especially those with 8p/VPS37A deletion.

## Key facts

- **NIH application ID:** 10879199
- **Project number:** 2R01CA222349-06A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** HONG-GANG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,500
- **Award type:** 2
- **Project period:** 2018-08-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879199

## Citation

> US National Institutes of Health, RePORTER application 10879199, Non-canonical Caspase-8 Activation on Autophagosomal Membranes (2R01CA222349-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879199. Licensed CC0.

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