Proteostasis (blue): Competitive binding of misfolded conformers to the molecular chaperone BiP activates one or more ER UPR sensors (ATF6, IRE1, PERK), initiating signaling to upregulate chaperones via three pathways: (i) ATF6p90 cleavage to ATF6p50 in the Golgi; (ii) IRE1 endoribonuclease activity for splicing XBP1; and (iii) PERK phosphorylation of eIF2α, repressing translation and upregulating ATF4. Proteins refractory to refolding are retrotranslocated from the ER and targeted to the 26S proteasome for degradation by the UPS, via the ERAD process. UPS inhibition can promote the accumulation of cytosolic protein macroaggregates in the aggresome via a microtubule-dependent manner. Autophagy and mitophagy (purple): The autophagosome-lysosome system targets cytosolic protein aggregates (macroautophagy) and dysfunctional organelles, such as mitochondria (mitophagy), for degradation. Ubiquitin-binding receptors, such as p62/SQSTM1, recognize K-48–linked polyubiquitinated protein aggregates or K-63–linked polyubiquitin-tagged mitochondrial outer membrane proteins (initiated by PINK1 recruitment of the E3 ligase parkin). LC3 binding envelopes ubiquitinated cargo and leads to elongation of isolation membranes (phagophores) and maturation into autophagosomes. Fusion with LAMP1⁺ lysosomes results in an acidified and functional autophagolysosome (autolysosome) that degrades the internalized content. Telomere maintenance (orange): Telomere length relies on the interaction between the multiprotein shelterin complex (end protection), the telomerase holoenzyme (elongation), and the DNA helicase RTEL1. Shelterin is composed of telomeric repeat binding factors 1 and 2 (TRF1 and -2), Tin2, TPP1, Rap1, and POT1. Key telomerase components include a reverse transcriptase subunit (TERT), an RNA template (TERC), and dyskerin. PARN promotes TERC RNA maturation. Not depicted is the CST complex. This figure was adapted with permission from Mulugeta et al. (46).