The role of BEACH-proteins in selective autophagy
Autophagy occurs at a basal level in most tissues, but can also be induced in response to a multitude of physiological and pathological situations.
Illustration: Peter Holland
About the project
Recent studies have highlighted the capacity of this pathway to specifically eliminate unwanted structures as aberrant protein aggregates, damaged organelles and invading pathogens and thereby protect against various diseases, such as neurodegeneration and cancer. The molecular mechanisms involved in regulation and execution of selective types of autophagy still remain elusive.
We have recently identified ALFY (Autophagy-linked FYVE protein) as being an important adaptor protein for selective autophagy of aggregate-prone proteins associated with Huntington’s and Parkinson’s disease. ALFY interacts with the ubiquitin-binding autophagy receptor p62 and links ubiquitinated proteins to the core autophagic machinery through its interactions with Atg5 and PI3P.
The interaction of ALFY with p62 was found to require a BEACH (Beige and Chediak Higashi) domain near its C-terminus, a domain also found in seven other human proteins. The BEACH domain is highly conserved, but neither its function nor any interacting proteins are known. BEACH domain containing proteins are generally very large (300-430 kDa) and although several of them have been linked to disease their cellular functions are poorly characterized. We have preliminary evidence that several BEACH proteins colocalize and interact with p62. Thus, binding to p62 might be a general feature of the BEACH domain, which may indicate an involvement of several BEACH proteins in selective autophagy.
The proposed project aims to
- further investigate the role of ALFY in selective autophagy,
- characterize the BEACH-p62 interaction and
- elucidate the role of other BEACH proteins in autophagy.
An approach combining state-of-the-art genomics, imaging and proteomics technologies with clinically relevant systems and cell biological models, will be used to address these questions.
The Research Council of Norway