Hindawi Publishing Corporation International Journal of Cell Biology Volume 2012, Article ID 189794, 8 pages doi:10.1155/2012/189794 Review Article Alternative Macroautophagic Pathways Katrin Juenemann and Eric A. Reits Department of Cell Biology and Histology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Correspondence should be addressed to Katrin Juenemann, k.junemann@amc.uva.nl and Eric A. Reits, e.a.reits@amc.uva.nl Received 18 October 2011; Accepted 19 January 2012 Academic Editor: Kim Finley Copyright © 2012 K. Juenemann and E. A. Reits. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Macroautophagy is a bulk degradation process that mediates the clearance of long-lived proteins, aggregates, or even whole organelles. This process includes the formation of autophagosomes, double-membrane structures responsible for delivering cargo to lysosomes for degradation. Currently, other alternative autophagy pathways have been described, which are independent of macroautophagic key players like Atg5 and Beclin 1 or the lipidation of LC3. In this review, we highlight recent insights in indentifying and understanding the molecular mechanism responsible for alternative autophagic pathways. 1. Introduction Autophagy, which is highly conserved from yeast to human, is a cellular degradation pathway that delivers cytoplasmic substrates to lysosomes for subsequent degradation. In contrast to the Ubiquitin-Proteasome System (UPS), which directly degrades monomeric proteins in the cytoplasm or nucleus, autophagy targets a wide spectrum of sub- strates including long-lived proteins, protein aggregates, and organelles towards lysosomes for subsequent degradation. In mammalian cells, autophagy occurs under basal conditions but can be stimulated by various stress conditions including starvation, hypoxia, and treatment with apoptosis-inducing compounds like rapamycin. In addition to its role in maintaining cellular homeostasis, autophagy is implicated in a wide range of physiological and pathological conditions, including early embryological development, clearance of pathogens, tumor suppression, and antigen processing and presentation [1]. In order to target cytoplasmic proteins to the lysosomes, several autophagic pathways exist, including microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. While micro- and macroautophagy can occur both in eukaryotes, plants, and fungi, CMA has only been observed in mammals. Microautophagy is the direct engulfment of cytoplasm or whole organelles by invagination or protrusion of arm-like structures of the lysosomal membrane. Here, the sequestration of cytoplasmic cargo occurs directly at the vacuole surface [2–5]. The second type of autophagy is CMA, which selectively degrades speciﬁc cytosolic proteins containing a pentapeptide motif (KFERQ) that is recognized by the heat shock cognate protein 70 (Hsc70) [6, 7]. The chaperone-substrate complex subsequently binds the lysosome through interaction with the receptor Lamp-2a on the lysosomal membrane [8]. Upon delivery by Hsc70, the substrate protein is unfolded before crossing the lysosomal membrane and lysosomal Hsc70 pulls the substrate into the lysosomal matrix where it is degraded by proteases [9]. The last but main type of autophagy is macroautophagy. Here, double-membrane vesicles, termed autophagosomes, are formed and sequester portions of cytosolic content or intact organelles (such as mitochondria) [10]. These autophagosomes are subsequently transported in a dynein-dependent manner along microtubules and fuse with endosomes or directly with lysosomes to form autolysosomes, resulting in breakdown of their contents by hydrolytic enzymes [11]. Macroautophagy is the major cellular pathway to recycle cell components including long- lived proteins and organelles, thereby providing nutrients for the eukaryotic cell, and it is activated under nutrient starvation. Additionally, macroautophagy is essential for development, cell survival, and tissue-speciﬁc processes [12, 13]. The initiation of autophagosome formation starts with the phagophore (autophagosome precursor), and re- cent studies indicate that the source of the membrane is