4.8 Article

Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis

Journal

AUTOPHAGY
Volume 19, Issue 1, Pages 54-74

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2022.2059170

Keywords

Autophagy; degradation; ferroptosis; inhibitor; mechanotransduction; pancreas; phosphorylation

Categories

Ask authors/readers for more resources

This study identifies HPCAL1 as a novel autophagy receptor for the selective degradation of CDH2 during ferroptosis. Depletion of CDH2 increases susceptibility to ferroptotic death. The phosphorylation of HPCAL1 and the non-classical LC3-interacting region motif play key roles in the autophagic degradation of CDH2. A ferroptosis inhibitor is found to suppress HPCAL1 expression. Inhibition of HPCAL1 prevents ferroptosis-induced tumor suppression and pancreatitis in mouse models.
Selective macroautophagy/autophagy maintains cellular homeostasis through the lysosomal degradation of specific cellular proteins or organelles. The pro-survival effect of selective autophagy has been well-characterized, but the mechanism by which it drives cell death is still poorly understood. Here, we use a quantitative proteomic approach to identify HPCAL1 (hippocalcin like 1) as a novel autophagy receptor for the selective degradation of CDH2 (cadherin 2) during ferroptosis. HPCAL1-dependent CDH2 depletion increases susceptibility to ferroptotic death by reducing membrane tension and favoring lipid peroxidation. Site-directed mutagenesis aided by bioinformatic analyses revealed that the autophagic degradation of CDH2 requires PRKCQ (protein kinase C theta)-mediated HPCAL1 phosphorylation on Thr149, as well as a non-classical LC3-interacting region motif located between amino acids 46-51. An unbiased drug screening campaign involving 4208 small molecule compounds led to the identification of a ferroptosis inhibitor that suppressed HPCAL1 expression. The genetic or pharmacological inhibition of HPCAL1 prevented ferroptosis-induced tumor suppression and pancreatitis in suitable mouse models. These findings provide a framework for understanding how selective autophagy promotes ferroptotic cell death.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available