Reading stuff I want to remember

• Nature cell biology paper Gatica et. al (2018)?


  Mitophagy is induced by loss of mitochondrial membrane potential.

  Normally:

  • PINK1 imported into matrix and cleaved by proteases normally and released for degradation through N-end rule pathway.

  Damaged state:

  • PINK1 stabilized on outer mitochondrial membrane --> autophoshorylated --> phosphorylates other substrates MFN1/2 and PARKIN .
  • Parkin then links phospho-ubiqiutin chains to OMM proteins --> amplifies further accumulation and recruits more PARKIN to do so.
  • P62/ SQSTM1 and OPTN bind LC3 --> autophagy occurs.
• News and Views Schuck (2016) ?


  SEC62 acts as autophagy receptor when liberated from SEC62/63 complex interacts w lipid anchored LC3 on the phagophore to produce autophagosome. This type of autophagy occurs when recovered from ER stress.

  FAMB134B induced autophagy occurs during starvation.

  
  

  Unfolded protein response triggers ER membrane expansion and increased level of ER chaperones and folding machinery + induces ERAD pathway.
• The reticular homology domain contains two transmembrane segments separated by linker and two conserved amphipathic helices
• Lysine residues get ubiquinated
• Ubiquitination

  Accelerates membrane curvature, faster transition to bicelle to closed vesicle with ubiquitination
• Effects of ubiquitination

  • Promotes receptor clustering
  • Membrane remodelling
• Ubiquitin moieties


  Enable trans-interactions at the RHD to form clusters
• Stabilisation of RHD clusters

  Induces membrane budding
• E3 ligase AMFR is recruited to ER-phagy receptor cluster and ubiquinates FAM134B
• Cluster formation process

  1. Clusters formed

  2. Cluster growth

  3. Remodel ER
• ATG contributes to autophagosomal membrane and membrane supply, pIP3 recruits ATG2-18 autophagy proteins to allow membrane elongation
• Selective autophagy is ATG8 dependent and must have an LC3 interaction region/LIR

  Recruit membrane receptors like SQSTM1
• Cruvature creation mechanistics? Nature Cell biology - Mizushima (2018)

  autophagic membrane bends while expanding into cup shape.

  Hypothesis 1: proteins on outer surface produce cup-shaped structure and contain curvature sensing domains + membrane lipids create autophagosomal membrane curvature

  Hypothesis 2: actin fibres inside expand autophagosomes with capz-dependent acitn polymerisation needed for membrane shaping

  BENDING = ENERGETICALLY EXPENSIVE
• Autophagy is invovled in degradation of oncogenic proteins + mutantsTP53, P62 + PML-RARA, and BCR-ABL1.

  Cancer cells depleted of ULK1/BECN1/ATG5 accumulate increased amount of mutant TP53.

  p62 has oncogenic function --> role in transduction of RAS-elicited signals + activation of feedforward loops using NFKB from oncogenic stress.

  AUTOPHAGY limits oncogensis by limiting p62 availability
• BRAF in autophagy is mutated in melanoma and activates MTORCI via ERK/TSC2/RHEB signalling --> induces hyperactivation + ER stress and triggers autophagy
• ATG5 is ubiquin ligase thats downregulated in melanoma cells, factor needed for autophagy