Selective autophagy mediated by TRIM proteins

The autophagy pathway promotes cellular and organismal health by selectively eliminating unnecessary and potentially harmful cytoplasmic contents. This process, known as ‘selective autophagy’, involves coordinating autophagy substrate recognition with activation of cellular machinery involved in autophagosome biogenesis and in autophagosome-lysosome fusion. The purpose of this project is to address fundamental questions about how selective autophagy works. Our scientific premise is that members of the tripartite motif containing (TRIM) protein family are essential actors in selective autophagy that coordinate all steps of the process. Our prior studies have shown that multiple TRIMs contribute to the selective autophagic degradation of both proteins and damaged organelles, including mitochondria and lysosomes. However, the detailed mechanistic basis for TRIM-mediated selective autophagy remains unknown for any TRIM, and it is not clear whether all TRIMs act similarly to carry out selective autophagy or whether different TRIMs employ different mechanisms. We hypothesize that TRIMs may utilize similar mechanisms in their selective autophagy functions. To test this hypothesis, we will first comprehensively dissect how one TRIM acts in selective autophagy, using TRIM5- mediated autophagic degradation of damaged mitochondria (mitophagy) as a model (Aims 1 & 2). Our studies will address how TRIM5 is activated by mitochondrial damage and how TRIM5 then activates the autophagy machinery to initiate mitophagy. Results from these aims will provide a roadmap for investigating if similar mechanisms are used by other TRIMs to initiate selective autophagy. In Aim 3, we will uncover the mechanism employed by TRIM27 in mitophagy and TRIM16 in the autophagic elimination of damaged lysosomes (lysophagy), asking whether essential aspects of TRIM5-mediated mitophagy are also employed by these TRIMs in their selective autophagy functions. We will also address the possibility that TRIM5 and TRIM27 act cooperatively in mitophagy. While TRIM5 and TRIM27 are similar proteins with the same selective autophagy substrate, TRIM16 is more distantly related. Finding that TRIM16-mediated lysophagy is mechanistically similar to mitophagy mediated by TRIM5 and TRIM27 would support the concept that there is a unified mechanistic paradigm for TRIM-mediated selective autophagy. This application is founded on extensive published and preliminary data and is supported by our research team’s expertise in applying proteomics, biochemistry, protein structure analysis, and correlative light electron tomography to the study of autophagy. Completion of this project will advance our understanding of the mechanisms of selective autophagy. Because defects in autophagy are increasingly associated with chronic diseases affecting the brain, heart, eyes, and liver, as well as various cancers, our studies may enable the development of targeted therapies by modulating specific selective autophagy pathways. Project Number: 1R01GM158808-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Michael Mandell | Institution: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR, ALBUQUERQUE, NM | Award Amount: $517,014 | Activity Code: R01 | Study Section: Cell Structure and Function 1 Study Section[CSF1] View on NIH RePORTER: https://reporter.nih.gov/project-details/11364045