Role of the HOIL-1L E3-ligase during lung injury

Dada

 

Dr. Laura Dada; Northwestern University

January 26 at 12:20pm in the Fralin Auditorium, Fralin Hall 102

Hosted by Dr. Daniel Capelluto

 

The covalent attachment of ubiquitin to target proteins is one of the most prevalent post-translational modifications. Recently, a novel RING E3 ligase complex was described: Linear Ubiquitin Assembly Complex (LUBAC). LUBAC connects ubiquitin molecules in a novel head-to-tail fashion via the N-terminal methionine residue, generating non-degradative linear chains. LUBAC is a heteromeric complex composed of heme-oxidized iron-responsive element-binding protein 2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L–interacting protein (HOIP), and shank-associated RH domain-interacting protein (SHARPIN). The main described role of LUBAC-generated linear chains is the activation NF-κB downstream cytokines receptors. The E3 ligase HOIL-1L, through its ability to add K48 linked ubiquitin chains promotes protein degradation and thus  regulates processes independently of LUBAC.

Acute lung injury (ALI) remains a significant source of morbidity and mortality in the critically ill patient population.  During ALI, increased levels of HOIL-1L in the alveolar epithelium may result protective or deleterious depending of the type of ubiquitin chain generated. Hypoxia, the hallmark of acute lung injury, leads to the ubiquitination of PKCζ by HOIL-1L tagging it for degradation; promoting cell homeostasis and increasing survival. However, during Influenza A virus induced lung injury increased HOIL-1L leads to the stabilization of LUBAC and a dysregulated production of cytokines or “cytokine storm” which is an important contributor to host mortality.  A better understanding of the pathways activated by LUBAC and its components is crucial to clarify its contribution to specific diseases.

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Queisser_et_al-2014-.pdf HOIL-1L Functions as the PKCz Ubiquitin Ligase to Promote Lung Tumor Growth
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PNAS-2017-Magnani-E10178-86.pdf HIF and HOIL-1L–mediated PKCζ degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury
Dada Flyer

This seminar will NOT be livestreamed or recorded.