Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

Abstract

Selective autophagy entails cooperation between target recognition and assembly of the autophagic apparatus. Target recognition is conducted by receptors that often recognize tags, such as ubiquitin and galectins, although examples of selective autophagy independent of these tags are emerging. It is less known how receptors cooperate with the upstream autophagic regulators, beyond the well-characterized association of receptors with Atg8 or its homologs, such as LC3B (encoded by MAP1LC3B), on autophagic membranes. The molecular details of the emerging role in autophagy of the family of proteins called TRIMs shed light on the coordination between cargo recognition and the assembly and activation of the principal autophagy regulators. In their autophagy roles, TRIMs act both as receptors and as platforms ('receptor regulators') for the assembly of the core autophagy regulators, such as ULK1 and Beclin 1 in their activated state. As autophagic receptors, TRIMs can directly recognize endogenous or exogenous targets, obviating a need for intermediary autophagic tags, such as ubiquitin and galectins. The receptor and regulatory features embodied within the same entity allow TRIMs to govern cargo degradation in a highly exact process termed 'precision autophagy'.

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

“…LC3 proteins) and that knockdowns of autophagy factors (ATG7 or Beclin 1) or receptors ( p62, NBR1 and ALFY) can cause midbody accumulation. TRIM17 has the potential to link these separate autophagy-related systems together along with the autophagy-activating kinase ULK1 in its active form, consistent with the concept of 'precision autophagy' proposed for other TRIMs (Kimura et al, 2016). In addition to TRIM17, we identified three other TRIMs (TRIM21, TRIM47 and TRIM76) that also contribute to the autophagic removal of midbodies.…”

“…Recent studies have implicated the TRIM family of proteins (Reymond et al, 2001) as both autophagy receptors that directly bind to their substrates (Kimura et al, 2015;Mandell et al, 2014;Niida et al, 2010) and as autophagy regulators (Kimura et al, 2015;Mandell et al, 2014;Barde et al, 2013;Yang et al, 2013), thus potentially being positioned to couple target specificity with autophagy induction or inhibition (Kimura et al, 2016). Several TRIMs such as TRIM5α, TRIM6, TRIM20, TRIM21 and others have been demonstrated to promote autophagy by assembling the key autophagy regulators ULK1 and Beclin 1 in their activated states (Kimura et al, 2015;Mandell et al, 2014).…”

TRIM16 suppresses the progression of prostate tumors by inhibiting the Snail signaling pathway

“…Since XNF7, the first member of TRIM family to be cloned and identified in 1997 (8), over 70 TRIM proteins have been found in the human genome to date (9). TRIM proteins play differing roles in cellular function including differentiation, transcription, cell cycle regulation, innate immunity and cell migration (10).…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…While occupying pivotal roles during host defense against microbes, induction of tolerance, antigen‐presentation, and tissue differentiation, a key function of autophagy pathways is to maintain a well‐balanced proteostasis and provision of metabolic building blocks and energy sources in response to nutrient deprivation and other cellular stressors248, 249, 250, 251, 252 As opposed to the proteasomal system, autophagy, in addition to removing aberrant proteins, aids in the removal of defective or excess mitochondria, lysosomes and peroxisomes and keeps, thereby, homeostasis on the level of macromolecules and whole organelles alike 253, 254, 255, 256. Consequently, defective autophagy pathways have been ascribed a pathological role in degenerative diseases of the brain236, 237, 257 and emerging evidence implicates autophagy in the pathoetiology of IBM.…”