4.8 Article

Phosphorylation of KRT8 (keratin 8) by excessive mechanical load-activated PKN (protein kinase N) impairs autophagosome initiation and contributes to disc degeneration

Journal

AUTOPHAGY
Volume 19, Issue 9, Pages 2485-2503

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2023.2186099

Keywords

Autophagosome initiation; intervertebral disc degeneration; keratin 8; phosphorylation; Protein kinase N

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Excessive mechanical load is a key factor in the development of mechano stress-induced pathologies such as intervertebral disc degeneration (IDD). This study demonstrates that conditional knockout of Krt8 within nucleus pulposus cells exacerbates load-induced IDD, while overexpression of Krt8 enhances the cells' resistance to overloading-induced apoptosis and degeneration. Additionally, the study reveals that the phosphorylation of KRT8 plays a crucial role in inhibiting the trafficking of RAB33B and suppressing autophagosome initiation, contributing to IDD.
Excessive mechanical load (overloading) is a well-documented pathogenetic factor for many mechano stress-induced pathologies, i.e. intervertebral disc degeneration (IDD). Under overloading, the balance between anabolism and catabolism within nucleus pulposus (NP) cells are badly thrown off, and NP cells undergo apoptosis. However, little is known about how the overloading is transduced to the NP cells and contributes to disc degeneration. The current study shows that conditional knockout of Krt8 (keratin 8) within NP aggravates load-induced IDD in vivo, and overexpression of Krt8 endows NP cells greater resistance to overloading-induced apoptosis and degeneration in vitro. Discovery-driven experiments shows that phosphorylation of KRT8 on Ser43 by overloading activated RHOA-PKN (protein kinase N) impedes trafficking of Golgi resident small GTPase RAB33B, suppresses the autophagosome initiation and contributes to IDD. Overexpression of Krt8 and knockdown of Pkn1 and Pkn2, at an early stage of IDD, ameliorates disc degeneration; yet only knockdown of Pkn1 and Pkn2, when treated at late stage of IDD, shows a therapeutic effect. This study validates a protective role of Krt8 during overloading-induced IDD and demonstrates that targeting overloading activation of PKNs could be a novel and effective approach to mechano stress-induced pathologies with a wider window of therapeutic opportunity.

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